Combined Topiramate and Metformin Pharmacotherapy for Second-Generation Antipsychotic-Induced Weight Gain in Pediatric Bipolar Disorder and Aggression

Abstract

Chief Complaint and Presenting Problem

M. was an 8-year-old boy referred to an inpatient child and adolescent psychiatry (CAP) service for a 3-week history of escalating aggression, suicidal ideation, and low lethality suicide attempts.

History of Present Illness

Three weeks before admission, M. had begun to exhibit escalation of irritability, mood lability, and aggression, which culminated in threats of suicide and an attempt of choking himself with a telephone cord in the presence of his mother. During this time, M. became suddenly irritable and aggressive with little to no provocation, and frequently expressed homicidal ideation toward his sister when she teased him. During these times of intense frustration, he hit himself in the chest with limited response to redirection. He reported feeling “sad” and “frustrated,” and he expressed suicidal ideation as well.

Mother reported that M. was waking frequently in the middle of the night to pace about the home with limited ability to return to sleep. Two days before admission, M. had an altercation with his sister during which he threatened to “rip her throat out.” He then tied a phone charging cord around his own neck, so tight that it left marks, which had to be forcibly removed by his caretaker. He repeated this behavior when frustrated with limit setting later in the day, and proceeded to say, “I'm angry and want to kill myself.” M.'s verbal expressions of suicidal ideation continued to escalate over the ensuing 2 days. This prompted his mother to bring him to a community hospital's emergency department for evaluation, and from there he was later admitted to the inpatient CAP unit.

Psychiatric History

M. had been evaluated in the past and carried prior diagnoses of attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and unspecified language disorder. At ages 5 and 6 years, he underwent two prior psychiatric admissions for aggressive behavior toward his sibling and peers at school, including stabbing a peer with a pencil. M. had been treated with several medications for behavioral outbursts and ADHD in the past, including stimulants and antipsychotics. Mother did not recall the details.

On admission, M. was being treated by his developmental pediatrician with aripiprazole 6 mg AM, and clonidine 0.1 mg AM and 0.15 mg PM for his impulsivity, and aggressive behavior, and had reportedly been stable for ∼18 months.

Although effective in reducing symptoms, M.'s regimen contributed to significant weight gain. In the year before admission, M.'s aripiprazole was decreased from 6 to 4 mg daily by his developmental pediatrician due to his weight gain and symptom improvement. Of note, mother also often held the morning dose of clonidine due to sedation during the school week; there was reportedly limited opportunity for follow-up appointments that may have contributed to difficulties in discussion of adverse effects.

Developmental History

Mother reported no medical problems associated with the pregnancy or delivery. In early childhood, M. was diagnosed with an unspecified language disorder and received speech therapy in school. Per his outpatient psychiatric provider, M. had difficulty with expressive language, and on testing had borderline verbal abilities. M. was not known to have other developmental delays. M.'s impulsivity and aggression were noted to interfere with classroom behavior and academic performance from an early age.

Educational History

At the time of admission, M. was starting third grade with an individualized education plan that included small classroom size (12:1:1), speech therapy, occupational therapy, and individual and group counseling.

Social History

M. lived with his mother and 7-year-old younger sister in an inner-city apartment. Father and father's extended family were not involved in his life at the time of admission, and historically had limited contact with M. M. and his sibling were often cared for by a babysitter after school until the evening.

Family History

Family history was positive for ADHD in M.'s mother, but no other psychiatric disorders. There was no known family history of suicidality.

Medical History

At the time of admission, M.'s only medical history was obesity: body mass index (BMI) was 26 kg/m², in the 99th percentile for age. The growth curves were not able to be retrieved from M.'s pediatrician.

Mental Status Examination

On his initial evaluation in the emergency department, M. displayed significant psychomotor agitation, including pacing. He appeared older than his stated age, with a large body habitus, and constricted but reactive affect. He was generally guarded about recent events, but he explained that he was brought in because “every time I get frustrated I want to kill myself” and “I can't control myself.” When asked about his suicidal statements and actions, he reported that when he is angry, he wants to die, and that he thinks about suicide “all the time.” His plan was not clear, although he made stabbing gestures toward his chest and identified his intent to be “dead and go to Heaven.”

Physical Examination

Physical examination and basic laboratory studies, including thyroid functions, complete blood count, hepatic function, and electrolytes, revealed no significant findings. Vital signs were within normal limits. However, M. was found to be in the 99th percentile for weight in his age group (weight 60.4 kg, height 1.52 m, BMI 26 kg/m²). Given the M.'s age and presentation, imaging was not warranted. Metabolic monitoring laboratories (cholesterol levels and hemoglobin A1c) were not collected by the admitting team, although may have been clinically useful in stratifying risk.

Hospital Course

On evaluation on the inpatient unit the next day, M. was calmer and more cooperative after sleeping intermittently overnight. He was able to discuss recent events and verbalize his needs, as well as an understanding of the hospital unit policies. He contracted for safety at that time.

Given his hyperactivity, insomnia, irritability, mood lability, suicidality, and aggression for several weeks, the team formulated a diagnosis of bipolar I disorder, with current episode representing a possible mania or mixed episode, in addition to the previous diagnosis of ADHD. M. was initially continued on aripiprazole 4 mg. Aripiprazole was titrated to 5 mg on hospital day 3 to address impulsivity, aggression, and mood lability (Table 1). Topiramate was chosen as an adjunct for its mood stabilizing affects and to address antipsychotic-related weight gain from aripiprazole.

Table 1.

Titration of Medication Doses by Hospital Day in Milligrams

Date	Topiramate AM	Topiramate PM	Aripiprazole	Clonidine AM	Clonidine midday	Clonidine PM	Metformin AM	Metformin PM
HD1	25	0	4	0.1	0.15	0.15	0	0
HD2	25	25	4	0.1	0.15	0.15	0	0
HD3	25	50	5	0.1	0.15	0.15	0	0
HD4	25	50	5	0.1	0.15	0.15	0	0
HD5	25	50	5	0.1	0.15	0.15	0	0
HD6	25	50	5	0.1	0.15	0.15	500	0
HD7	50	50	5	0.1 ER	0	0.1 ER	500	0
HD8	50	50	5	0.1 ER	0	0.1 ER	500	0
HD9	50	75	5	0.1 ER	0	0.1 ER	500	500
HD10	50	75	5	0.1 ER	0	0.1 ER	500	500
HD11	50	75	5	0.1 ER	0	0.1 ER	500	500
HD12	50	75	5	0.1 ER	0	0.1 ER	500	500
HD13	50	100	5	0.1 ER	0	0.2 ER	500	1000
HD14	50	100	5	0.1 ER	0	0.2 ER	500	1000
HD15	50	100	5	0.1 ER	0	0.2 ER	500	1000
HD16	75	100	5	0.2 ER	0	0.2 ER	500	1000
HD17	100	100	5	0.2 ER	0	0.2 ER	500	1000
HD18	100	100	5	0.2 ER	0	0.2 ER	500	1000
HD19	100	100	5	0.2 ER	0	0.2 ER	500	1000

Of note, clonidine was switched from immediate to ER on HD7.

ER, extended release; HD, hospital day.

After informed consent was obtained, topiramate was initiated at 25 mg daily and titrated to 100 mg twice daily at time of discharge (Table 1). To further mitigate the impact of second-generation antipsychotic (SGA)-induced weight gain, metformin was added starting at 500 mg daily and titrated to 500 mg qAM and 1000 mg qHS (Table 1). Both new medications were well tolerated, and side effects were not reported.

M. also continued treatment with immediate release clonidine 0.1 mg qAM and 0.15 mg qHS. Initially to reduce aggression and hyperactivity, M. was placed on a regimen of clonidine 0.1 mg in the morning, 0.15 mg at midday, and 0.15 mg in the evening. This was converted to the extended-release formulation for longer coverage, starting at 0.1 mg twice daily (BID) and titrated to 0.2 mg BID with good response for management of ADHD symptoms.

Over the course of his 18-day hospitalization, M. demonstrated reduction of aggression and impulsivity, correlating with changes to his medication and increased participation in psychotherapy on the unit.

Initially M. demonstrated very limited frustration tolerance, particularly in the setting of conflict with peers, characterized by tearful outbursts escalating to screaming and at times physical aggression toward peers. M. demonstrated mood lability and provocative behavior toward peers frequently during his hospitalization, requiring redirection and a structured behavioral plan to help him maintain safety and to reinforce improved emotional self-regulation. Although M. was able to be verbally managed on most occasions, one of these events on hospital day 12 required medication; diphenhydramine 50 mg by mouth (PO) was administered with good effect 2 hours after chlorpromazine 50 mg PO had not been effective.

Over the course of treatment, M. was able to demonstrate improved insight into his unsafe behaviors. M.'s outbursts, mood lability, and irritability improved: he was able to verbalize to a greater degree and to employ better coping skills. Mother and the treatment team noted a significant reduction in episodes of aggression—including frequency, intensity, and duration.

Early in the hospital course with the titration of topiramate, M. achieved resolution of his insomnia, sleeping through the night with few interruptions. M. also did not engage in any further suicidal gestures, nor did he express suicidal thoughts after initial interviews. With medication and staff interventions, M. was able to better participate in school classes, as well as individual and group therapies.

Nutritional counseling was provided to M. and mother during hospitalization. Notably, M. did demonstrate weight loss through the hospital course: weight was 60.4 kg on admission and 58 kg at discharge, and his weight loss was expected to continue in the outpatient setting.

M. was discharged to the care of his outpatient developmental pediatrician and a new psychotherapist at another hospital system.

Brief Formulation and Diagnosis

In summary, M. was an 8-year-old boy admitted for several weeks of worsening aggression, impulsivity, irritability, mood lability, homicidal and suicidal ideation, and gestures, with new onset insomnia and psychomotor agitation in the context of recent decrease in his aripiprazole due to weight gain.

Given the clinical picture of 3 weeks of insomnia with elevations in agitation, impulsivity, mood lability, aggression, and psychomotor agitation at night, M. was diagnosed with bipolar I disorder, episode manic on admission. M's suicidal ideation and sadness, explosive angry outbursts, and constricted and irritable affect rather than euphoric or expansive affect are mixed features typical of bipolar illness in children and adolescents (Singh 2008; Marangoni et al. 2015).

Although a diagnosis of bipolar disorder was supported, given M.'s past ADHD diagnosis and history of emotional dysregulation, his emotional lability, irritability, aggression, and suicidality may also be related to ADHD with deficient emotional self-regulation (DESR) rather than mania (Masi et al. 2021). Although diagnostically M. presented a mixed picture, it was felt that M.'s reverse neurovegetative symptoms and persistent episodic irritability were consistent with both diagnoses.

M. had significant biological and psychological risk factors for the development of bipolar disorder. The personal and family history of ADHD and diagnosis of ODD at the time of presentation put him at elevated risk for bipolar disorder (Marangoni et al. 2015). The decrease in SGA implemented 3 months before admission may also have been a risk factor for his presumed manic episode.

M.'s aggressive symptoms, mood lability, impulsivity, and suicidal ideation reduced as medications were titrated over the course of hospitalization. It is suspected that his aggression, insomnia, and impulsivity were improved by the combined mood stabilizing effects of aripiprazole and topiramate; however, these symptoms may also in part have been reduced by the structured clinical environment of the inpatient setting. Reduction of DESR in the context of his ADHD may have occurred in association with the increase and switch to long-acting clonidine.

Discussion

Antipsychotics, particularly SGAs, are commonly utilized in the management of psychotic and bipolar illness in children and adolescents, as well as for aggression, despite significant metabolic adverse effects (Daviss et al. 2016; Barker et al. 2018). Childhood obesity is a particularly negative outcome, and is a common and burdensome side effect in the long term for young patients (Chung et al. 2018).

The impact of SGAs on male youth in particular has been described (Rice and Walther 2020). SGAs impact androgen levels through elevation of prolactin levels, altering androgen-mediated neuroprotection and neurogenesis. Aripiprazole, a prolactin-sparing SGA, was chosen in this youth partially to reduce these risks. Nonetheless, weight-gain associated with aripiprazole induces increased adipose tissue and testosterone aromatization. Male children experience detrimental social as well as neurobiological effects from these alterations, and topiramate may provide an opportunity to attenuate these risks.

M. presented in the 99th percentile for weight, with weight gain associated with aripiprazole. The burden of his weight gain led to dose reduction in the months preceding his presentation, possibly contributing to decompensation. M.'s symptoms improved while on an increased dose, but the metabolic side effects he suffered needed to be addressed. His aggressive behavior in the classroom and at home could be understood as a protective affect against perceptions of vulnerability, partially mediated through increased obesity and feminization.

There are limited pharmacological options for addressing or preventing SGA-associated weight gain, but metformin and topiramate are important treatments to consider, and are increasingly studied for this purpose (Ellinger et al. 2010; Zhuo et al. 2018; Correll et al. 2020; Nikou et al. 2021).

To target the metabolic side effects of M.'s medication, the clinical team decided to utilize both metformin and topiramate for their complementary actions on metabolic syndrome and, therefore, weight gain. Metformin decreases blood glucose production in peripheral tissues and the liver, increases insulin sensitivity, and reduces blood cholesterol elevations, reversing key metabolic consequences of SGAs (Dayabandara et al. 2017; Wróbel et al. 2017). The peripheral action of metformin pairs well with the central action of topiramate, which acts through the central nervous system to improve insulin sensitivity by centrally stimulating insulin-mediated glucose uptake in muscle and adipose tissue through the hypothalamus (Coomans et al. 2013).

Topiramate also works to reduce appetite that facilitates weight loss; this is theorized to be related to increased efficacy of gamma-aminobutyric acid activation in leptin-responsive neurons that ultimately lowers appetite (Stanley 2012; Adan 2013; Czepiel et al. 2020). A recent meta-analysis (Zhuo et al. 2018) found that topiramate is the most effective medication to reduce BMI in patients on antipsychotic medications. In sum, both medications serve to promote weight loss in patients by multiple pathways, and in turn reduce other metabolic adverse effects such as hyperlipidemia and hyperglycemia.

There is increasing evidence in childhood for use of metformin for SGA-induced weight gain specifically, with multiple studies showing a significant decrease in BMI with metformin (Ellul et al. 2018; Correll et al. 2020). Although still considered off-label use in children, it is a well-studied approach to SGA-induced weight gain in adults, and generally well tolerated (Dayabandara et al. 2017).

Although it is efficacious and well studied, it is known that psychiatrists may be reluctant to prescribe this nonpsychotropic medication due to hesitation about prescribing guidelines, scope of practice, side effects, and “off-label” use. In response, a group in Australia created a prescribing tool for metformin to promote its use by psychiatrists (Smith et al. 2017). A similar approach may prove beneficial for child psychiatrists to more effectively and safely manage the negative consequences of SGA medication without unnecessary reliance on primary care.

Beyond its effects on weight, topiramate was chosen in this case because it has utility as an alternative or adjunct to SGAs for the treatment of impulse control disorders in children (Berlin 2008). Topiramate has off-label use in bipolar disorder for mood stabilization in bipolar mania, alone and in conjunction with other medications (Munshi et al. 2010; Simonetti et al. 2020; Nikou et al. 2021). Two retrospective chart reviews of children and adolescents diagnosed with bipolar disorder, of 25 and 26 total patients, respectively, have reported that topiramate was an effective adjunctive treatment in reduction of symptoms on the Clinical Global Impressions-Scale in manic, depressive, and mixed episodes (DelBello et al. 2002; Barzman et al. 2005; Munshi et al. 2010).

Although potentially helpful, topiramate is not without risk of cognitive side effects, including attention and working memory deficits, and is associated with increased risk of depressed mood and aggression (Moavero et al. 2017; Adachi et al. 2019). Given its efficacy for weight loss and impulse control disorders, for children such as M. topiramate's benefits may outweigh the risks.

There are a few limitations of our analysis of this case. First, the admission laboratory work did not include metabolic monitoring laboratories, though glucose was found to be 105 mg/dL on admission (mild elevation). M.'s obesity was evidence of a metabolic syndrome produced by antipsychotic medication, but this was unconfirmed by laboratory studies. Knowledge of the birth weight and availability of M.'s growth curves would have provided additional context, as would longitudinal follow-up.

Furthermore, M.'s symptoms may be consistent with a picture of emotional dysregulation associated with ADHD as well as bipolar disorder; diagnoses in children can sometimes not be firmly made without clinical assessment over time. Finally, the structure and support of the inpatient unit may have itself led to a decrease in the patient's symptomatology, in addition to medication titration.

Conclusion

Although an effective and appropriate treatment for children with major mood disorders, aggression, and impulsivity, SGAs are undoubtedly contributing to the burden of obesity and metabolic syndrome in already high-risk children. This topic has become particularly pertinent with the increasing number of children with aggression, especially young males, who are treated with SGAs despite growing concerns over childhood obesity (Daviss et al. 2016; Barker et al. 2018).

The burden of childhood obesity on the health of the individual and on societal resources is increasingly well known (Chung et al. 2018). As pharmacotherapy may contribute to this epidemic, it is in part our responsibility as child and adolescent psychiatrists to reduce the burden of such common adverse effects on our patients (Daviss et al. 2016; Barker et al. 2018). This case shows a potential approach to utilize topiramate for its mood stabilizing effects in such cases, as well as for its weight loss potential. This, in addition to metformin, may help to reduce the metabolic burden of SGAs in pediatric patients.

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