Abstract
Chief Complaint and Presenting Problem
R. was a 15
History of Present Illness
R. had been experiencing symptoms of depression and anxiety characterized by depressed mood, anhedonia, decreased energy, decreased motivation, initial insomnia, feeling excessively anxious, restlessness, and intermittent muscular tension for 3–4 years with associated intermittent passive suicidal ideation, usually triggered by interpersonal conflicts with friends and significant others. He tried to cope with these emotions on his own but was unable to, and after feeling overwhelmed, he disclosed his symptoms to his mother, and was promptly connected to a therapist.
Parents reported that R. had voiced suicidal ideation on numerous occasions but had never acted on these thoughts. They also noted that he had no friends at school but had a few friends online. Parents reported that since breaking up with his girlfriend, he had become more aggressive and irritable and had been experiencing more severe mood swings.
Psychiatric History
During his first therapy session a few months before referral, R. disclosed suicidal thoughts in the context of a recent breakup with his girlfriend. He was subsequently referred for his first inpatient admission. R.'s symptoms reportedly improved during that admission with fluoxetine 20 mg daily, however, it gradually worsened after discharge.
One week after discharge at an outpatient appointment, he reported ongoing depressive symptoms, derealization, and depersonalization, and was started on aripiprazole 2 mg daily to augment fluoxetine.
He was evaluated a month later in the outpatient clinic and at that time reported a plethora of symptoms including worsening depression, restlessness, anger, irritability, impulsivity, and depersonalization. At that visit, his fluoxetine was increased to 40 mg daily and aripiprazole was continued at 2 mg daily.
One week after his clinic evaluation, he was referred to the psychiatric emergency department for suicidal and homicidal ideation toward his ex-girlfriend with whom he had broken up a few months prior. He was reported to experience increasing suicidal ideation without a plan or intent, and he began having intrusive thoughts about hurting his ex-girlfriend. These thoughts evolved into a yearning to kill his ex-girlfriend; he denied any plan or intent.
After disclosure of homicidal ideation to his therapist, he was referred for evaluation in the psychiatric emergency department under a professional certificate and was subsequently admitted. At the time of admission, he reportedly was adherent to his home medications prescribed as fluoxetine 40 mg/day and aripiprazole 2 mg/day.
Developmental History
R was his mother's second pregnancy, and he was a planned conception. Mother received prenatal care and used no substances or medications during the pregnancy. R. was the product of an uncomplicated pregnancy, and he was delivered through cesarean section at 40 weeks. Birth weight was 3.63kg and there were no complications after delivery.
Mother reported that R. had attained all his developmental milestones, including walking and language acquisition, on time.
Educational History
R was enrolled in public high school and was in the 10th grade at the time of his admission. He was in the gifted program at school, receiving all A's and B's, and was enrolled in a few advanced classes.
Social History
R. was born in a large diverse city in the southeast United States. Both parents were originally from South America. He lived with both parents and his paternal grandmother. He reportedly was getting along well with parents. R. had one older brother, age 21 years, who left home for university 2 years ago.
Parents separated when he was 11 years old, but they subsequently reunited. Approximately 1 year before admission, R. and his family moved to a new residence, and this was a difficult transition for him.
R. had no history of substance use, physical, emotional, or sexual abuse, and no reported history of sexual behavior; however, recently he had ended a romantic relationship with his girlfriend. His hobbies included music, drawing, and art.
Family History
Family history was significant for diabetes in father, bipolar disorder in a maternal cousin, and dementia in a maternal aunt.
There was no other known family history of psychiatric illness and no known history of suicide.
Medical History
R. had no history of significant medical illness or hospitalization. There was no history of head injury, surgery, or previous brain imaging. Immunizations were up to date, and he had no medication allergies.
Medication History
R. had been treated with fluoxetine 20 mg daily during hospitalization in the past year. Aripiprazole 2 mg was added to address continued depressive symptoms, derealization, and depersonalization. Fluoxetine was increased to 40 mg daily and aripiprazole was continued at 2 mg daily 1 week before his most recent admission.
Mental Status Examination
On initial examination, R. appeared his stated age, was well nourished, and well developed. He appeared anxious and dysphoric, but was alert and oriented, to person, place, and time. He made occasional eye contact. His speech was clear and coherent with appropriate speed and volume. Before assessment, he was observed constantly pacing about; he appeared to be emotionally distressed and was crying and holding his head in his hands.
He had a dysphoric mood with restricted affect. He reported intrusive thoughts of wanting to kill his girlfriend, and a recent desire to act on these thoughts but appeared distressed by these thoughts. His thought process was organized and linear. He denied auditory or visual hallucinations and did not appear internally preoccupied; no paranoia was elicited. He endorsed both suicidal and homicidal ideation and exhibited poor insight and judgment at the time of assessment.
Brief Formulation
In summary, R. was a 15-year-old adolescent boy with a psychiatric history of major depressive disorder, anxiety disorder, and borderline personality traits referred to the psychiatric emergency department for involuntary evaluation of suicidal and homicidal ideation toward his ex-girlfriend with whom he had recently broken up.
Predisposing factors included R.'s borderline personality traits such as sensitivity and emotional dysregulation related to interpersonal conflict, bipolar disorder on the maternal pedigree, parental separation when he was a preteen, and relocation to a new residence. There were also some parent–child conflicts due to differences in approach to addressing mental health. Precipitating factors included the departure of his older brother from the household to attend college, and his recent break up with his girlfriend. Perpetuating factors included attendance at the same school as his girlfriend after they broke up, thus having to cope with daily reminders of his former relationship. Protective factors included his intelligence, adherence to treatment, and his sense of responsibility to his family.
Multiaxial Diagnoses
Anxiety disorder, unspecified
No suspicion of intellectual disability
Treatment Course
On admission, R. was continued on fluoxetine 40 mg daily. His aripiprazole was discontinued due to marked restlessness suspected to be akathisia; he was started on propranolol 10 mg daily for akathisia. Olanzapine 2.5 mg at bedtime was started for his increased aggression and intrusive homicidal ideation, and hydroxyzine 50 mg up to four times a day as needed for anxiety. Melatonin 5 mg at bedtime as needed was prescribed for insomnia.
R. had stable vital signs; routine laboratories were grossly within normal limits except for his high-density lipoprotein that was elevated at 73 (normal 40–60) and vitamin D 25-OH (normal range >30 nmol/L) that was low at 25.7 nmol/L. Other laboratories including triglycerides, calculated low-density lipoprotein, cholesterol, urine toxicology A1c, free T4, thyroid-stimulating hormone, vitamin B12, folate, and point-of-care-testing glucose were all within normal limits.
On the second day of admission, R. reported continued suicidal and homicidal ideation but did experience some improvement in anxiety with PRN (as needed) hydroxyzine. He also reported a decrease in severity in his levels of restlessness and aggression and was hopeful that things would improve during his admission. Olanzapine was increased to 5 mg at bedtime with good tolerability.
On the third day of admission, R. reported elevated anxiety, restlessness, and aggressive thoughts. He continued to report suicidal and homicidal ideation toward his girlfriend. He reported questionable auditory hallucinations, but he did not appear to be responding to internal stimuli. Fluoxetine was increased to 50 mg daily and olanzapine was continued at 5 mg at bedtime.
On the fourth day of admission, he reported improvement in his anxiety and improvement in his suicidal and homicidal ideation, but expressed concerns about continued intrusive impulsive thoughts. He experienced an episode of hypotension accompanied by dizziness; as he was no longer showing signs of akathisia, his propranolol was discontinued.
On the fifth day of admission, R. reported feeling better with improvement in suicidal and homicidal ideation and was tolerating his medications well. Fluoxetine was increased to 60 mg daily and olanzapine was continued at 5 mg at bedtime.
On the sixth day of admission, R. reported continued improvement in his mood with resolution of his suicidal and homicidal ideation. He reported no adverse effects of fluoxetine and olanzapine.
R. was discharged on day 7 on fluoxetine 60 mg/day, olanzapine 5 mg at bedtime, and hydroxyzine 50 mg two times a day as needed for anxiety. He was seen for a postdischarge follow-up appointment 3 weeks later with sustained improvement in mood and anxiety. He was enrolled in an intensive outpatient program 5 days per week and individual therapy and continued to report benefit from his medications without adverse effects.
Discussion
This case illustrates an interesting hospital course of an adolescent with worsening depression, suicidal ideation, new onset homicidal ideation, and akathisia seemingly after initial treatment with aripiprazole. It may provide unique insight into potential adverse effects of a second-generation atypical antipsychotic. This case also demonstrates the nuance of choice when prescribing antipsychotic medications and the importance of recognizing and screening for psychosocial factors when making clinical decisions.
Previous research has shown the prevalence of suicidal and homicidal ideation in adolescent populations is higher in those with psychopathology. Suicidal ideation and completed suicide rates are elevated in adolescents with depression, dysthymia, anxiety, attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder (Greydanus and Calles, 2007; Martin et al., 2016). Homicidal ideation is increased in adolescents with mood disorders, such as depression and bipolar disorder, and emotional and behavioral disorders including anxiety, attention-deficit/hyperactivity disorder, and conduct disorder (Sun et al., 2022; Vaughn et al., 2020).
R. had a diagnosis of depression and was initially treated with fluoxetine that is Food and Drug Administration (FDA) approved for depression in the pediatric population. There is a well-documented history regarding the use of fluoxetine in the pediatric population and the potential increased risk of suicidal ideation and attempts, but not completed suicide. Ultimately, extensive reviews of relevant studies suggest that the risk–benefit ratio favors the use of antidepressants in adolescents (Soutullo and Figueroa-Quintana, 2013). In this case, it is unlikely that the prescribed selective serotonin reuptake inhibitor (SSRI) was causally related to suicidal ideation in R. since these thoughts were present before the use of fluoxetine.
Aripiprazole is an atypical antipsychotic indicated for treatment of schizophrenia, bipolar disorder, and irritability associated with autistic disorder in the pediatric population (Kirino, 2012). Recently, aripiprazole has been used to treat bipolar depression and refractory unipolar depression in children and adolescents due to its antidepressive, anxiolytic, and emotion-stabilizing effects (Ciray and Tuncturk, 2021; Hellerstein et al., 2008; Kirino, 2012). Adverse effects of aripiprazole include extrapyramidal symptoms, hyperprolactinemia, weight gain, metabolic disorders, and sedation, which are also common in other atypical antipsychotic drugs (Doey, 2012; Kirino, 2012).
Studies have demonstrated that aripiprazole is generally tolerable due to its advantages of relatively lower rates of weight gain, sedation, and hyperprolactinemia than other atypical antipsychotics and placebo (Correll et al., 2017; Shapiro et al., 2003).
However, a more common extrapyramidal symptom that has been associated with aripiprazole is akathisia, a subjective feeling of restlessness and inability to sit still with the urge to move the lower extremities (Doey, 2012; Kirino, 2012). Akathisia may begin early in atypical antipsychotic treatment, but onset may also be delayed (Shapiro et al., 2003). Higher doses of aripiprazole are reported to be associated with increased risk of developing akathisia (Shapiro et al., 2003). Lower doses of aripiprazole are effective as adjunctive therapy to SSRI/serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants in treatment of depression.
R. was started on 2 mg aripiprazole while he was concurrently taking fluoxetine 20 mg/day. Studies have shown that aripiprazole is an effective adjunct to SSRI/SNRI antidepressant therapy in treatment-refractory depression due to its partial agonist activity at dopamine D2 and serotonin 5HT1A receptors and potent antagonist activity at serotonin 5HT2A receptors. Aripiprazole and its relatively lower likelihood of weight gain, sedation, and parkinsonism side effects are due to its low affinity to alpha-1 adrenergic, histamine H1, and muscarinic M1 receptors (Hellerstein et al., 2008).
Aripiprazole 10–20 mg/day had no adverse interactions or effects on the pharmacokinetics with concurrent use of fluoxetine 10–20 mg/day in various studies using aripiprazole as an adjunct therapy in major depressive disorder (Pae et al., 2011). Aripiprazole was prescribed for R. for new-onset pseudopsychotic and depressive symptoms after partial improvement in depressive symptoms on fluoxetine. R. then developed worsening suicidal ideation and new homicidal ideation after concurrent treatment with fluoxetine and aripiprazole. Although he was prescribed a low dose of aripiprazole, concomitant use of fluoxetine might have significantly increased its plasma level through inhibiting CYP450 2D6 (Bostankolu et al., 2015).
Previous literature has shown an association between akathisia and aggressive behavior and physical aggression, manifest by both suicidal and homicidal ideation (Chow et al., 1997; Drake and Ehrlich, 1985; Shear et al., 1983; Stubbs et al., 2000). Although there is no sufficient literature demonstrating that antipsychotic-induced akathisia is associated with aggressive behavior, studies suggest that antidepressant-induced akathisia is. One study that examined patients who were diagnosed with akathisia or serotonin toxicity after taking psychiatric medication found that 8 (n = 129) had committed homicide and many more became extremely violent while on antidepressant medication (Lucire and Crotty, 2011).
The study describes one subject with a similar clinical picture as our patient; the subject was a 16-year-old male treated with fluoxetine for depression, struggling at school, and his girlfriend had left him. During hospitalization for suicidal ideation, he exhibited akathisia and then killed his therapist (Lucire and Crotty, 2011).
Studies have also reported an association between aripiprazole and suicidal ideation. A Dutch case report in 2005 was the first to document suicidal tendencies as a side effect of aripiprazole; the authors highlighted five patients who had started aripiprazole and reported feelings of agitation and akathisia; all these patients then developed suicidal thoughts, and three attempted suicide. The authors noted that none of the patients had previously attempted suicide and additionally, the suicidal thoughts disappeared after discontinuation of aripiprazole (Scholten and Selten, 2005).
Although different, both suicidal and homicidal thoughts encompass forms of aggression, with suicidal ideation representing inwardly directed aggression, and homicidal ideation representing outwardly directed aggression. The Dutch case report may provide insight into the effect of aripiprazole in R. It is crucial to acknowledge, however, that conflicting evidence exists and that certain studies assert that, in comparison with other antipsychotic medications, aripiprazole does not carry an escalated risk of hospitalization, self-harm, or suicide (Montastruc et al., 2019).
Aripiprazole was discontinued in our patient due to his akathisia and his treatment was augmented with olanzapine, given its established effectiveness as a mood stabilizer, and substantiated by evidence endorsing its off-label application as an adjective therapy for depression and mood symptoms (Spielmans et al., 2013). In addition, a study reported that the combination of olanzapine and fluoxetine yielded superior improvement in individuals with major depressive disorder compared with the effects of each agent alone (Shelton et al., 2001). Augmentation with olanzapine was much more significant and yielded lesser adverse effects in R. when than aripiprazole.
Although some studies show no difference in adverse effects between the medications, other studies revealed that aripiprazole carried almost a 50% higher risk of akathisia than a combination of older second-generation antipsychotics such as olanzapine (Komossa et al., 2009; Thomas et al., 2015). This elevated risk associated with aripiprazole could be attributed to its receptor profile. As previously mentioned, aripiprazole acts as both an agonist on the 5-HT2C receptor and an antagonist on the 5-HT2A and 5-HT2B receptors.
In contrast, olanzapine acted as an antagonist at all three 5-HT2 receptor subtypes (Zhang et al., 2006). Although the complete mechanism may yet to be fully understood, the difference in the medications' pharmacological profile might contribute to the risk of adverse effects including akathisia.
In conclusion, this case report underscores the imperative for clinicians to extend evaluation to encompass a broad spectrum of clinical factors. Beyond the traditional focus on suicidal and/or homicidal ideation, a comprehensive assessment should consider potential medication-related adverse effects. Notably, potentially elevated risk of aripiprazole-associated akathisia—and subsequent aggression-driven behaviors—emphasizes the necessity of heightened vigilance.
Footnotes
Disclosures
B.J.C. is on the scientific advisory board of Teva/Nuvelution, received honoraria from the American Academy of Child and Adolescent Psychiatry, Partners Healthcare, Harvard Medical School/Psychiatry Academy, grant support from Florida Children's Medical Services, and research support from Teva/Nuvelution, Emalex, and NIMH. She is on the National Advisory Board of Skyland Trail, is cochair of the medical advisory board of the Tourette Association of America (TAA), a nonpaid position, and on the speakers' bureau for the TAA-CDC Partnership. K.B., Y.B., K.T., and M.S. have no disclosures.