Treatment of Bipolar Disorder in an Adolescent with Autistic Disorder: A Diagnostic and Treatment Dilemma

Chief Complaint and Presenting Problem

G. is a 15-year-old Caucasian male referred to the Emergency Department by his outpatient psychiatrist for admission secondary to ongoing mood lability and disorganization.

History of Present Illness

G.'s mother reported that he has experienced a recurrent mood disturbance that begins in early spring for the past four years. These disturbances of mood were characterized by decreased need for sleep, increased energy, increased and inappropriate masturbation, mood lability (laughing one minute, then crying the next), and increased provocative and attention-seeking behaviors. G. would also become more aggressive, grabbing hold of adults' arms and throwing objects. By June each year, G. would become more sullen and withdrawn. He would state, “I am sad and I don't know why.” G.'s teacher of two years stated that since the beginning of summer school, prior to his referral, G. had been acting “like a bump on a log.” He appeared to be interested only in his MP3 player, and his academic performance had declined. G. was subsequently referred to the inpatient unit by his outpatient psychiatrist for mood stabilization.

At the time of referral, G. and his parents reported that G. was experiencing depressed mood, irritability, crying spells, anhedonia, possible feelings of worthlessness (“I am stupid”), insomnia, and decreased appetite with a ten-pound weight loss in six weeks. G. denied suicidal ideation and denied recent or remote self-injurious behaviors. G.'s parents reported that his energy was “high at times and low at other times.” He also exhibited elevated mood at times. G. displayed hypersexuality as evidenced by increased and indiscriminate masturbation, and increased goal-directed activities.

The family denied that G. had experienced inattention and restlessness. At that time, he had become oppositional, argumentative, and easily angered. He also purposely annoyed others at times. G. denied anxiety symptoms, suspiciousness, thought blocking, thought control and thought insertion. His parents noted that he talked to characters from the book series Harry Potter on occasion. Otherwise, there was no report of hallucinations. His parents also reported that G.'s speech was disorganized at times.

Past Psychiatric History

At age 18 months, G. was evaluated by a developmental pediatrician for unclear reasons. At that time, he was reported to exhibit a delay in developmental milestones that was believed to be secondary to malnutrition due to a pancreatic enzyme deficiency. At age 2 and a half years, G. was evaluated for autism, and showed a global delay in gross motor and fine motor skills, cognition, and speech and language skills. He was diagnosed with pervasive developmental disorder, not otherwise specified. G. was considered higher functioning compared to other children diagnosed with autistic spectrum disorders. He was reported to exhibit good eye contact and was more socially reciprocal. His family noted that he communicated well verbally, but needed some assistance with activities of daily living.

At age 5, G.'s parents began to suspect a mood disorder. His parents reported that G. experienced periods during which he became provocative and impulsive. He was reported to touch and pinch people, and then run away, and would break things. At age 10, G. was evaluated by a psychiatrist who believed that he had a mood disorder, possibly rapid cycling bipolar disorder.

G. had one prior admission to a psychiatric inpatient unit at age 10 years. Lithium was started at that time. He was hospitalized on a medical unit initially at age 12, and again at age 13. A diagnosis of neuroleptic malignant syndrome (NMS) was suspected at that time, as well as malignant catatonia. According to the consulting neurologist, G. became rigid, febrile, tachycardic, hypertensive, and his creatine phosphokinase (CPK) level was elevated in the 1000s while taking aripiprazole. He was treated supportively with intravenous fluids.

Despite previous psychological testing, G.'s IQ is unknown because testing has been unreliable due to his developmental delays. He has received several brain magnetic resonance imaging (MRI) scans and several electroencephalography (EEG) tests. G's MRI scans have shown consistent and stable diffuse cortical atrophy and bilateral parietal lobe white matter changes. EEG tests have shown spike and slow-wave activity in the bilateral parietal lobe regions that correlates with the findings on the fMRIs.

G. has had trials of several psychotropic medications, all of which were complicated by adverse effects. He has taken several antidepressants, including fluoxetine, citalopram, buproprion, venlafaxine, sertraline, and escitalopram, but was not able to tolerate therapeutic doses. He has been reported to become activated on antidepressants, resulting in agitation, impulsivity, “silliness,” and aggression. G. has also taken several mood stabilizers, including lamotrigine, lithium, valproate, oxcarbazepine, carbamazepine, levetiracetam, and topiramate. While taking lithium twice in the past, G. experienced severe nausea, vomiting, diarrhea, and confusion, which led to a question of lithium toxicity despite a normal lithium level. When valproate was tried in the past, it was also discontinued due to concerns about development of pancreatitis, given G.'s history of pancreatic enzyme deficiency. However, he did not experience any adverse effects. The maximum dose of valproate was reportedly 125 mg twice a day.

G. has also had previous trials with neuroleptics, including risperidone, aripiprazole, olanzapine, zyprasidone, quetiapine, haloperidol, clozapine, perphenazine, and chlorpromazine. G.'s parents reported that he had become more aggressive while taking neuroleptics. They noted that his speech became garbled and somewhat disorganized; in addition, he was reported to develop enuresis and abnormal buccolingual movements on both typical and atypical neuroleptics. His parents also reported that he developed priapism twice in the past while taking sertraline and quetiapine.

G. has taken other classes of medications including amphetamine, guanfacine, methylphenidate, clonazepam, gabapentin, and inositol. He was reported to become disinhibited on benzodiazepines in the past.

Lamotrigine was started when G. was age 10, discontinued that same year for unclear reasons, and restarted at age 12. G. has continued taking lamotrigine since then. His outpatient psychiatrist was in the process of tapering lamotrigine and aripiprazole to eventually discontinue them at the time of admission.

Medications at the time of admission included lamotrigine 150 mg twice a day, aripiprazole 1 mg every morning, and melatonin 3 mg at bedtime as needed for insomnia.

Developmental History

G. is the product of a full-term pregnancy, and weighed 3.86 kg at birth. Delivery was induced and he required suction after delivery. Apgar scores at birth were 9 and 9.

G. began speaking first words at age 9 months. He began speaking in phrases at 3 years of age. However, mother reported a pause in G.'s speech production between the ages of 9 months and 3 years, during which, at times, he did not speak at all. He began walking at around age 2 years, and was toilet trained between 4 and 5 years of age. He received a diagnosis of autism at that time.

Educational History

G. attends an elementary school for children with autistic disorder. He completed kindergarten through second grade there, and was subsequently home schooled. He returned to school at age 11 years. He was due to start the ninth grade in the fall prior to admission.

Social History

G. lives with his mother and father who provide 24-hour supervision. There is no history of abuse or neglect. There is no history of domestic violence exposure, and he has no access to firearms.

His parents report that G. has some friends, but only in the school setting. His favorite activity is listening to his MP3 player.

Family History

G.'s mother and father are Caucasian and both have earned masters degrees. G.'s mother has a history of fibromyalgia and depression treated with escitalopram. G.'s father has no history of psychiatric illness and no history of substance abuse. G. has no siblings.

Extended family history on the maternal side is significant for mood disorders and suicide. History includes a great-grandfather with bipolar disorder who committed suicide by hanging, a great-great-aunt who committed suicide, a great-great-uncle who committed suicide, a cousin with depression, an uncle with “situational depression,” a second cousin with bipolar affective disorder, an additional second cousin with bipolar affective disorder, a great uncle who was hospitalized for depression, a second cousin who committed suicide at age 16, and another second cousin who was hospitalized for depression and possibly has bipolar disorder. G. also has a third cousin with a pervasive developmental disorder, and an additional third cousin with obsessive compulsive disorder and possible Asperger's disorder.

Extended history on the paternal side is significant for a cousin with schizophrenia and a second cousin with bipolar disorder who is currently incarcerated.

Medical History

G. receives routine care from his pediatrician. His immunizations are up to date. He was diagnosed with pancreatic enzyme deficiency at age 3 years and treated with Pancrease. This has since resolved, but his pediatric gastroenterologist is in the process of ruling out Shwachman-Diamond syndrome. He has had continued enuresis and wears pull-up diapers.

G. has no history of head injury or loss of consciousness. He is allergic to dairy products, but has no known drug allergies. Current medications include Miralax 17 g every morning, a multivitamin, and fish oil twice a day.

Mental Status Exam on Admission to State Hospital

G. was casually groomed with fair hygiene, dressed in a T-shirt and shorts. He exhibited poor eye contact. He was listening to loud music on his headphones and was restless and became frustrated when asked to remove them. G.'s speech was difficult to understand, and he responded in only single word answers. His volume of speech was loud at times and soft at other times. His mood was “okay,” but he appeared distressed with labile affect. G. smiled at one moment and then quickly looked agitated and angry at another. His thought process was disorganized. G. denied suicidal ideation, homicidal ideation, or passive wishes to die. His cognition was hard to assess; however, he appeared to be oriented to person and situation. His insight and judgment were considered poor.

Hospital Course

Upon admission, G. exhibited aggressive behaviors including throwing and breaking objects (i.e., crayons and a MP3 player). Aggressive behaviors were mostly unprovoked. G. also exhibited mood lability. He masturbated frequently, and in the presence of others. G. also slept very minimally, if at all, most nights. These symptoms were thought to be consistent with a mixed manic and depressed state.

Given G.'s history of NMS while taking aripiprazole, the treatment team initially decided to avoid treatment with antipsychotics. He was placed on lorazepam 1–2 mg as needed for agitation and aggression and received a maximum dose of 4 mg in a 24-hour period. His aggression escalated to charging, hitting and kicking staff members, necessitating multiple locked door seclusions. He masturbated more frequently, and exhibited a worsening of enuresis and occasional encopresis. Due to these symptoms of disinhibition, lorazepam was discontinued. G. was then placed on quetiapine 50 mg as needed and his aggression was more adequately controlled. On quetiapine, G. was also more re-directable and responded better to behavioral interventions. However, G. developed dysarthric speech and was difficult to understand. Sialorrhea also worsened.

G.'s outpatient psychiatrist was in the process of decreasing aripiprazole at the time of admission, and the treatment team therefore discontinued aripiprazole. As the team continued to taper G.'s lamotrigine and continued quetiapine at 25 mg by mouth twice a day, the patient's mood symptoms improved. He became much less irritable with fewer aggressive behaviors, slept through the night, and masturbated much less frequently. Addition of quetiapine resulted in reduction of aggression and possible improvement of mood symptoms. However, increasing quetiapine was limited by sedation and the development of dysarthric speech. At discharge, G.'s only medication was quetiapine 25 mg by mouth twice a day.

Brief Formulation

In summary, G. is a 15-year-old Caucasian male with a family history significant for extensive bilineal affective illness and suicides, pervasive developmental disorder, and anxiety disorder. He has a personal history significant for autism and a cyclic mood disturbance yearly for the past four years. G. was referred for hospitalization by his outpatient psychiatrist for treatment of the mood disturbance.

Target symptoms at admission included decreased need for sleep, increased energy, increased and inappropriate masturbation, mood lability, increased provocative and attention-seeking behaviors, and irritability with increased aggression. There was also concern that G. appeared withdrawn at times, disinterested in anything other than his MP3 player, and had experienced an academic decline. Given his presentation and significant genetic loading, it was evident that G. had a cyclic mood disorder. G.'s presenting symptoms were most consistent with a diagnosis of bipolar disorder, most recent episode mixed without psychotic features, in the context of an existing diagnosis of autism. It was not felt that Schwachman Diamond Syndrome was contributing psychiatric or behavioral manifestations to the clinical picture.

Multi-Axial Diagnoses

Discussion

This case illustrates the complex intersection of the development of a major mood disorder in adolescence in the context of autism, an early onset pervasive developmental disorder. Children with autism may often experience problematic emotional reactions and behaviors superimposed on the cardinal features that define autism. In the past, there was a tendency to attribute all psychiatric problems in children with autism to autism itself (Skokauskas & Gallagher 2010). Disturbances of emotion, attention, activity, and thought, and associated behavioral problems occur in children with autism of all ages (Lainhart 1999). There is a growing body of evidence to suggest that a significant percentage of patients with autism spectrum disorder (ASD) have comorbid psychiatric disorders that may cause significant clinical impairment and result in an increased burden of illness. Therefore, comprehensive evaluation and accurate diagnosis of comorbid psychiatric disorders in children with ASD is critical.

Several studies have evaluated the epidemiology of ASD and comorbid disorders and report that depression is the primary psychiatric comorbid disorder reported in association with ASD (Ghaziuddin et al. 1992; Ghaziuddin et al. 1998). The prevalence of bipolar disorder in children with autism has not been clearly established, although some studies found high rates for this comorbidity (Frazier et al. 2002; Komoto et al. 1984; Wozniak et al. 1997; Munesue et al. 2008). Several studies suggest that ASD may share common vulnerability genes with bipolar disorder (Munesue et al. 2008).

A challenge in the diagnosis of comorbid psychiatric disorders in children with ASD is the presence of language deficits at baseline. Children with autism are often not able to articulate mood symptoms. Affective flattening and social withdrawal observed in autistic children may be difficult to differentiate from depressive illness. Few studies elucidate how mania manifests itself in individuals with ASD (Skokauskas & Gallagher 2010).

Another important concern in the ASD population is the possibility of increased sensitivity to medication adverse effects, as well as decreased efficacy. There is limited evidence that children with autism may need lower doses of some psychotropic medications due to the potential for increased adverse effects (Handen et al. 2000). In addition, medications such as the selective serotonin reuptake inhibitors (SSRIs) may be less effective in children with ASD as compared to children without ASD (King et al. 2009). Both G.'s brain abnormalities and developmental disability may also render him more vulnerable to adverse effects of psychotropic medications (Wink et al. 2010; King et al. 2009). However, more studies are needed to further evaluate tolerability of psychotropic medications in this population.

A mood disorder secondary to a general medical condition was considered as a diagnostic possibility, given the patient's fMRI scans, and spike and slow wave activity in both parietal lobes shown on EEG tracings. Temperolimbic epilepsy, for example, may cause manic symptoms. Neurology was consulted during the hospitalization; their opinion was that G.'s symptoms were more likely related to a mood disorder than a seizure disorder. They agreed that treatment with an antiepileptic, such as valproate, would be indicated whether his symptoms were due to a seizure disorder or primary bipolar disorder.

The inpatient treatment team initially planned to treat with valproate. However, because of his history of pancreatic enzyme deficiency, G.'s gastroenterologist was very concerned about the possibility of the development of severe/hemorrhagic pancreatitis. In addition, the history of pancreatic enzyme deficiency also rendered hepatic effects of valproate more risky. However, G. had been stable without the need for pancrease supplements, and recent gastrointestinal work-ups had been negative. A trial of valproate may be warranted with very careful monitoring in coordination with the gastrointestinal specialist.

Prior to admission, G. had been treated with several neuroleptics, including both typical and atypical agents, but nearly all trials were limited by adverse effects. The history of NMS in association with aripiprazole was of concern; relative to other second generation atypicals, aripiprazole may be associated with more extra-pyramidal symptoms. Risperidone, olanzapine, ziprasidone, haloperidol and clozapine had all been tried, and unfortunately, all were associated with significant adverse effects. The resulting dilemma was whether an antipsychotic could be safely reintroduced.

Inpatient treatment focused on medication management to target mood and aggression. Mood symptoms improved markedly once lamotrigine was decreased to 75 mg daily and quetiapine was added.

In conclusion, with regard to treatment options for G., as with any other patient, a careful risk/benefit analysis is mandatory in decision-making. There is little evidence in the extant literature on the pharmacokinetics, pharmacodynamics or adverse-effect profiles of medications used for young patients in the autistic population. Additional placebo-controlled trials and studies of safety and tolerability of psychotropic medications in the autistic population are needed.