Optimizing Clozapine Benefit While Minimizing Adverse Effects with Concomitant Fluvoxamine Treatment in an Adolescent with Schizoaffective Disorder

Chief Complaint and Presenting Problem

K. was a 16-year-old young man admitted for worsening depressive symptoms with an inability to care for himself and bizarre behaviors at home who stated “I'm very depressed.”

History of Present Illness

K., the fourth of six children, lived in public housing with his family in a major metropolitan area. Diagnosed with autism spectrum disorder (ASD) and developmental delays at the age of 4 years, he was enrolled in 10th grade in a specialized school. Medical history was notable for a head injury after a motor vehicle accident at age 5 years. Psychiatric history was notable for four hospitalizations, including 1 year in a state institution, for psychotic symptoms culminating in a diagnosis of schizoaffective disorder. After state hospitalization, K. was transferred to a locked residential treatment facility for ∼1 year.

Since discharge from the facility, K. had limited psychiatric care with intermittent outpatient follow-up. He remained on medication prescribed at the facility, which included aripiprazole 30 mg twice a day and doxepin 75 mg at bedtime. Despite adherence to the regimen, K. experienced a marked deterioration in his functioning. He had an increase in the frequency and intensity of long-standing symptoms, including depressed mood, crying episodes, irritability, feelings of guilt, disrupted sleep, frequent nightmares, low energy, anhedonia, poor appetite, and lack of motivation. He had also been exhibiting a decline in self-care, with poor personal hygiene. In addition to these symptoms, K. had also exhibited increasingly bizarre behaviors at home, frequently pacing the halls loudly, and calling friends in the middle of the night. These symptoms led to referral for admission to an acute inpatient psychiatry unit.

Upon admission, K. endorsed feeling depressed and having feelings of guilt regarding effects of his depression on his family, but denied suicidal or homicidal ideation. He denied perceptual disturbances, reporting that he last experienced auditory and visual hallucinations ∼1 year ago. During initial interview, K. was frequently tangential and disorganized, exhibiting loosening of associations but no overt delusions. K. reported religious and somatic preoccupations; he made frequent comments about witchcraft, the crucifix, and the devil, and endorsed stomach pain with constipation, headache, nausea, and an intermittent sensation that his head and face were excessively hot. He demonstrated some paranoia directed toward the treatment team, and often appeared suspicious of benign comments and questions. K. and his family denied manic symptoms, including decreased need for sleep, increased energy, pressured speech, grandiosity, or increased distractibility.

Psychiatric History

K.'s first contact with a mental health professional occurred at age 5 years when he was diagnosed with an ASD. Primary symptoms of concern included head banging, agitation, and aggressive behavior, such as throwing a chair in anger at home, and banging on windows in school. He received early intervention with applied behavioral analysis and occupational and speech therapies through an individualized family support plan, followed by services through an individualized educational plan.

At age 11 years, K. was referred for outpatient psychiatric treatment of depression and anxiety. By age 13 years, psychotic symptoms had emerged; for example, mother reported that K. was talking to himself and yelling, “go away,” while protecting his face. He had exhibited bizarre behaviors such as collecting garbage out of garbage trucks, presenting a bag of rocks to his mother while insisting that it was “bones and blood,” and making “holy water” out of a milk container. At age 13 years, he was hospitalized at an acute inpatient psychiatric unit after telling his teacher, “I want to kill myself.” He made subsequent suicidal statements resulting in three additional hospitalizations from the ages of 12 to 15 years. The fourth admission led to a transition into a state hospital with a course that lasted 1 year, followed by entry into a residential treatment facility.

At 16 years, while in residential treatment, K. exhibited delusions centered around religious and sexual themes. He had also reported auditory hallucinations of nonspecific words spoken in a foreign language, as well as visual hallucinations of “figures” and “faces with scary eyes.” At the residence, K. had frequently appeared internally preoccupied and distractible, and showed impaired reality testing. He also believed that he had witnessed a murder in the hotel across from the family's apartment, which did not occur, according to mother. K.'s paranoia seemed to worsen at times of acute stress, such as perceived conflicts with others.

Developmental History

Mother reported no pregnancy or birth complications. His mother reported that K.'s birth weight was 5 pounds, 5 ounces, placing him in the 3–5th percentile. K. had a history of global developmental delay including speech, motor, and social delays, with remediation, including early intervention services, committee on preschool special education services, and committee on special education services. He reportedly did not walk until 18 months and did not speak until age 4 years. Psychological testing from 2014 revealed a full-scale intelligence quotient of 87.

Educational History

At the time of admission, K. was a 10th grade student in an 8:1:1 special education class setting and had been attending school despite his symptomatology. He received speech therapy, occupational therapy, and counseling at school.

Social History

K. lived with mother and one adult brother, 4 years his senior, in public housing in a major metropolitan area. He had five siblings, including three older brothers and two younger sisters. Father had minimal involvement in K.'s life and his mother was the sole legal guardian. K. reported that his father was “verbally abusive” at times and their relationship was often strained. K. received respite care services three times per week, as well as functional family therapy. Child services had been involved beginning when K. was 2 years old, secondary to inadequate guardianship and neglect, but there was no active case at the time of K.'s hospitalization. K. had a few close friends from school and enjoyed practicing karate for fun, although he had received no formal instruction in the martial arts.

Pertinent Family History

The brother who lived with K. and his mother had experienced significant lead exposure, a prior suicide attempt, and a history of psychosis treated with olanzapine and risperidone. Maternal grandmother was hospitalized many times for depression and had been treated with electroconvulsive therapy, as well as olanzapine and valproic acid. A maternal uncle had made a prior suicide attempt.

Mother denied any other family history of psychiatric illness or substance use.

Medical History

Medical history was significant for seasonal asthma well controlled with an albuterol inhaler as needed, and lead exposure. Mother denied recollection of receiving any treatment for the lead exposure.

K. sustained a head injury when he was hit by a motorcycle at 5 years of age. The incident resulted in a transient loss of consciousness for <5 minutes. His physical examination was unremarkable and he did not sustain any major injuries. He was hospitalized on a pediatric unit for 2 days for observation and discharged home without any intervention.

K. had no known allergies.

Medication History

From initiation of psychiatric care at age 11 years until K.'s admission and transfer to a state hospital facility, he had only received trials of olanzapine and mirtazapine, with details of timing and dosing unknown. At age 13 years during the admission that led to his state hospitalization, K. was started on risperidone and lithium. During his state hospitalization, diphenhydramine 50 mg p.o. b.i.d. was added and he was treated with lithium 600 mg p.o. b.i.d. and risperidone 1 mg p.o. q.a.m. and 2 mg p.o. q.h.s. At his residential stay, his risperidone was first cross-tapered to aripiprazole at 15 mg p.o. b.i.d. Lithium was tapered to discontinuation, and a trial of doxepin was initiated to target poor sleep. He received several doses of chlorpromazine 75 mg approximately every other day during this time period. In this setting, K. was titrated up to aripiprazole 30 mg p.o. b.i.d. without significant response to his agitation and paranoia. At this point, he transitioned from the residential facility to the inpatient unit, where his aripiprazole and mirtazapine were tapered to discontinuation by hospital day 4 and his initiation of clozapine and fluvoxamine was begun.

Mental Status Examination

K. was a well-developed teenage boy with facial acne, disheveled, unshaven, and malodorous. He was attentive and cooperative, but somewhat oddly related. He exhibited no behavioral abnormalities or evidence of extrapyramidal symptoms. His speech was spontaneous, but somewhat dysarthric. Although he reported feeling “very depressed” in the emergency department (ED), on the unit he reported feeling “much better,” and had a positive, although somewhat blunted, affect. His thought process was very concrete, with occasional disorganization and loosening of associations. He perseverated about medication changes, frequently repeating the same questions even after receiving direct responses. He also exhibited persecutory delusions, paranoia, and hyper-religiosity. He denied perceptual abnormalities and did not appear to be responding to internal stimuli. He also denied suicidal or homicidal ideation.

K. was oriented but appeared to have a limited fund of knowledge, consistent with his known cognitive impairment. He demonstrated fair insight into the symptoms he was experiencing, and judgment adequate, in that he was willing to work with the team to develop a treatment plan.

Treatment Course

After admission, informed consent for clozapine was discussed with and obtained from mother to target K.'s psychosis. Clozapine was chosen, given failed trials of several antipsychotics, including risperidone, olanzapine, and aripiprazole, none of which resulted in improvement in symptoms sufficiently to improve K.'s quality of life. In addition, discussion and informed consent for fluvoxamine were obtained to target depressive symptoms and to impact clozapine pharmacokinetics.

Fluvoxamine inhibits the metabolism of clozapine to its inactive metabolite, norclozapine, thus resulting in a higher level of the active substrate at a lower medication dose. To carefully monitor safety of this intervention, serum levels of clozapine and norclozapine were measured every other day, and absolute neutrophil count (ANC) was monitored weekly, with results listed in Table 1.

During the initial titration of clozapine, K. reported mild sedation and dizziness. Vital signs were within normal limits. Titration schedule was slowed to address his complaints, and he did not experience further side effects. Throughout his hospital stay, K. was adherent to medications. Although dosing considerations most closely followed clinical symptoms, serial serum levels informed dosing.

During the first week of admission, K. continued to exhibit significant signs of psychosis: he remained religiously and spiritually preoccupied, and continued to exhibit paranoid ideation and disorganized thinking with tangentiality, loose associations, and occasional clang associations. Clozapine was titrated at a slow rate despite active symptoms to prevent too rapid a rise in clozapine levels while fluvoxamine was titrated (see Table 1 for a timeline of dosing titration and serum levels).

In the following 2 weeks, dosing titration remained cautiously slow and included some periods of tapering as serum levels of clozapine rose rapidly. The risks of this rate of rise were considered to be outweighed by the benefit of providing a more response to K.'s symptoms. Nevertheless, there were two events of concern. On day 15, K. punched a wall after witnessing his roommate get into a fight with a peer on the unit. A hand X-ray after the incident was normal. On day 17, K. threatened to kill his roommate after being teased, but was able to use coping skills learned on the unit to self-regulate. He quickly apologized after the incident and acknowledged that he did not mean it. These behaviors coincided with clearance of aripiprazole.

Serum levels became supratherapeutic, although the patient denied adverse effects, including sedation, sialorrhea, hypotension, tachycardia, and constipation. Interestingly, norclozapine levels were persistently undetectable, potentially contributing to the lack of significant adverse effects despite the high serum clozapine levels. Fortunately, ANC remained stable throughout the course of the interventions.

At approximately the start of the fourth week, K.'s mood and psychotic symptoms significantly improved. He became much calmer, was less irritable and more organized. He participated in school, individual, and group therapy; learned new coping strategies; and gained insight. This occurred within the course of the fourth week (Table 1) through decrease in his clozapine dose to a mere 25 mg, which produced good symptom control with therapeutic levels. Mother was in agreement for discharge with the following regimen: clozapine 25 mg q.h.s. and fluvoxamine 300 mg q.h.s. He had no restrictions on home activity or diet and was scheduled to see his established psychiatrist and therapist the following business day.

Postdischarge Course and 16-Month Follow-Up

The transition from inpatient to outpatient setting revealed several challenges. After admission, K. was unable to obtain discharge medications due to inactive insurance and financial constraints. K. presented to the ED on the day of his scheduled follow-up appointment, 4 days after discharge, for help. He was assessed to be psychotic in the context of medication nonadherence, and exhibited symptoms including increased agitation and somatic preoccupations. Admission clozapine level was not detected. He was rehospitalized for retitration of medication and stabilization for 26 days during which fluvoxamine was retitrated to 300 mg q.h.s. and clozapine to 50 mg q.h.s. while insurance information was rectified. The dose of clozapine was increased from 25 mg as K. demonstrated physical aggression during this second admission.

At 16 months postdischarge, K. had been sufficiently adherent to outpatient follow-up with fluctuating symptom control. He had no further inpatient hospitalizations or ED presentations—a remarkable change after his multiple rehospitalizations when on alternative regimens or without access to the regimen.

However, there were challenges in the outpatient setting. During the initial months, adherence with level monitoring was tenuous; K. required retitration of clozapine due to missing one weekly blood draw and one failure to pick up medication from the pharmacy. After this adjustment, K. and mother asserted consistent medication adherence during collateral interactions. Nevertheless, there were several indications of inconsistent adherence that made continuation of the clozapine/fluvoxamine regimen questionable. After 6 months on this regimen, K.'s pharmacy intermittently reported that K. had not been picking up the fluvoxamine and/or clozapine, raising suspicion for missed doses of either or both medications. Furthermore, the clozapine level measured while on a 50 mg q.h.s. dose (583 ng/mL) dropped to 438 ng/mL after increasing the dose to 62.5 mg q.h.s. The discrepancy between K.'s report and other evidence regarding adherence posed a dilemma regarding whether and how to retitrate the medications.

Other challenges included difficulty engaging mother in attending appointments despite K. receiving the highest level of case management services available. As mother did not attend most appointments, K.'s psychiatrist accompanied him to almost all venipuncture appointments, as having an adult present with the minor was required. Furthermore, K. was evaluated in the ED ∼1 week after readmission for fever and cough, and diagnosed with atypical pneumonia, and treated with antibiotic and steroid medications. Subsequently, K. presented with symptoms of persistent cough and associated chest pain, thought to be an asthma exacerbation; however, given risk of myocarditis with clozapine, K. and mother were repeatedly referred to his pediatrician for medical work-up. Unfortunately, K. received medical follow-up many months later and these symptoms eventually resolved.

Over the course of outpatient treatment, symptom control fluctuated in the context of emerging adolescence, parent–child conflict, and inconsistent adherence with medication. Fluctuating symptomatology included irritability, supernatural- and religious-themed auditory and visual hallucinations, paranoia, preoccupations, nightmares with tenuous reality testing, and aggressive outbursts. Clozapine was increased at several times to a maximum of 75 mg for exacerbation of these symptoms. K. tolerated medication adequately, notable for initial excessive salivation that reportedly improved over time. Weight gain was noted as the dose increased, as was morning sedation. Split dosing was suggested, but adherence to b.i.d. dosing was even more challenging and, therefore, q.h.s. dosing remained.

Despite many challenges in the outpatient setting, overall symptom stability provided by clozapine and fluvoxamine as compared with prior regimens allowed K. to adhere to outpatient treatment and maintain therapeutic alliance. Although it remained difficult to cultivate a similar level of rapport with mother, she developed sufficient trust in the treatment team such that she was able to participate in the treatment.

Brief Formulation

In summary, K. was a 16-year-old adolescent boy with a history of ASD and schizoaffective disorder, depressed type, with multiple prior admissions, and 1 year of state hospitalization referred for worsening depressive symptoms, bizarre behavior, and an inability to care for himself. He displayed clear signs of a primary thought disorder superimposed over his intellectual disability, most notable for disorganized thinking and speech, religious delusions, and paranoia.

From a biopsychosocial perspective, biological contributions were numerous. Given a strong family history of psychosis and depression, K. was genetically predisposed to a primary psychotic disorder. Significant developmental delays, lead exposure, and a head injury at age 5 years may also have contributed to his presentation. Neuropsychological testing would be better able to evaluate for any residual effects of this injury and their potential contribution to his presentation, including whether he would meet criteria for a traumatic brain injury.

Psychosocial factors also played a significant role in K.'s presentation. Although engagement with early intervention services and supportive programs was a protective factor, concerns for adequacy of care in the home environment rendered K. vulnerable. The acute decrease in level of care after his abrupt departure from the residential program to a home environment with less structure and support was highly stressful.

Discussion

Childhood onset schizophrenia is a rare disorder, accounting for 0.1%–1% of all schizophrenic disorders when the onset is before 10 years of age, and 4% when the onset is before age 15 years (Remschmidt et al. 1994). There is a male predominance with impairments resulting from both positive and negative symptoms (Hafner et al. 1993). There is a historical nosological relationship between ASD and schizophrenia, as well as high correlations between ASD and schizophrenia spectrum disorders and possible common neural underpinnings (de Lacy and King 2013; Canitano and Pallagrosi 2017). In children and adolescents, similar to adults, antipsychotic medications are the mainstay of treatment (National Collaborating Centre for Mental Health (Great Britain) 2013).

Clozapine, the first atypical antipsychotic to be discovered, has been in use since the 1970s and consistently found to have superior therapeutic effects relative to both first- and second-generation antipsychotics (Kumra et al. 1996, 2008). Clozapine is potentially associated with numerous side effects, among them significant weight gain and metabolic abnormalities, and it is most notoriously for its potential to cause neutropenia. Although rare both in adults (Alvir et al. 1993) and in children and adolescents (Gerbino-Rosen et al. 2005; Midbari et al. 2013), the risk of agranulocytosis deters many clinicians from prescribing clozapine despite its proven efficacy (Gogtay and Rapoport 2008).

There have been some studies in the coadministration of fluvoxamine with clozapine in both adult and youth populations. This may be particularly appropriate with a patient like K. who had both depressive and psychotic symptoms, constituting a diagnosis of schizoaffective disorder.

Clozapine is metabolized through the cytochrome P450 system into its active metabolite, norclozapine (Schaber et al. 2002). Plasma levels of norclozapine, but not clozapine, are associated with some of the adverse treatment effects, including increases in serum glucose, triglyceride levels, and weight (Lu et al. 2004). A clozapine–norclozapine ratio of 2:1 or higher was found to be associated with increased efficacy and tolerability of clozapine in patients with treatment-resistant psychosis (Szegedi et al. 1999; Légaré et al. 2013). There appears to be benefit from interventions that modify the clozapine–norclozapine ratio so as to increase therapeutic effect while reducing adverse effects. This may be especially true for a patient with a depressive component for whom antidepressants could also target depressive symptoms.

Fluvoxamine is a selective serotonin reuptake inhibitor used since the 1990s (Westenberg and Sandner 2006). It is a well-known inhibitor of several cytochrome P450 enzymes that metabolize clozapine, such as CYP1A2, CYP3A4, and CYP2D6 (van Harten 1995). Inhibition of these enzymes results in increase in clozapine and reduction in norclozapine plasma levels, thus altering the clozapine–norclozapine ratio. By doing so, fluvoxamine can attenuate adverse effects observed in patients treated with clozapine (Lu et al. 2018).

Fluvoxamine use for this purpose should be undertaken with caution, however, as increased plasma levels of clozapine can lead to toxicity or severe neutropenia (Polcwiartek and Nielsen 2016). Owing to high variability of quantity and type of cytochrome P450 isoforms in the liver, predicting plasma clozapine concentration in an individual patient is challenging. Therefore, slow induction with low dosage and careful monitoring of plasma levels and ANC is recommended to ensure safety.

Few studies have examined the use of clozapine in conjunction with fluvoxamine in treating patients with refractory schizophrenia. To date there have been four published literature reviews (van Harten 1995; Westenberg and Sandner 2006; Légaré et al. 2013; Polcwiartek and Nielsen 2016) and three randomized controlled trials (Szegedi et al. 1999; Lu et al. 2004, 2018) that established the benefits of using clozapine with fluvoxamine; however, these trials were limited to adults. In addition, although the mechanism by which fluvoxamine enhances effects of clozapine has been established in adult observational studies (Schaber et al. 2002), no studies to date have evaluated this process in adolescents or children.

Literature (Häfner et al. 1993; Remschmidt et al. 1994; De Lacy and King 2013; Canitano and Pallagrosi 2017), chart reviews (Gerbino-Rosen et al. 2005; Gotay and Rapoport 2008; and Yalcin et al. 2016) and two randomized trials (Kumra et al. 1996, 2008) demonstrated therapeutic benefit and efficacy of clozapine in youth unresponsive to other antipsychotics, but to date no studies have examined how children and adolescents respond to the addition of fluvoxamine.

Taken together, our case report contributes important findings by demonstrating safety and therapeutic benefit of this regimen in an adolescent. The inpatient setting facilitated close monitoring and frequent dose adjustments necessary to ensure a safe and tolerable treatment result. At last follow-up, K. was stable in ongoing treatment in an outpatient setting, and had not required further hospitalization or residential treatment.