JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume 26, Number 1, 2016 ª Mary Ann Liebert, Inc. Pp. 74–77 DOI: 10.1089/cap.2016.29100.bjc
Advanced Pediatric Psychopharmacology
Staying Up at Night: Overlapping Bipolar and Obsessive-Compulsive Disorder Symptoms in an Adolescent with Autism Spectrum Disorder Presenters: Philip Cawkwell, BA,1 Ashley Lawler, MD,2 and Eleni Maneta, MD2 Discussant: Barbara J. Coffey, MD, MS3
Chief Complaint and Presenting Problem
to report some worsening in her mood again, and her psychiatrist added bupropion extended-release to her fluoxetine. This did not provide adequate relief, and S. was tapered off fluoxetine and started on venlafaxine, which was titrated up to 112.5 mg. S. did well for a few months, but during the winter holiday from school she decompensated, with worsening depression and anxiety. She was subsequently switched from venlafaxine to lamotrigine, because of both family history of bipolar disorder, and increased irritability that had been noted. Cognitive rigidity was also noted at that time, and ziprasidone 40 mg was added as a stabilizing agent. Although these medication changes seemed to improve her depression, the outpatient psychiatrist noted that S.’s anxiety had worsened again. S. and her mother agreed that S. had begun to decompensate rapidly in the 4 weeks prior to this current admission following the end of the school year. S. stated that she felt that she had had to ‘‘grow up’’ and apply for jobs and learn to drive, causing her anxiety to significantly worsen. She stated that she began to experience severe intrusive thoughts. Specifically, S. became fixated on the idea of someone stealing her identity, as she had to give out her social security number when applying for jobs. Although she maintained insight into the small likelihood of this happening, S. experienced increasing levels of distress over these thoughts, which impaired her ability to complete her applications. S. also began to have an increased fixation on germs and cleanliness; that is, excessively washing her hands and seeking reassurance about being clean. S.’s mother reported that in the context of S.’s recent decompensation, ziprasidone was increased to 80 mg daily, which led to worsening agitation and anxiety. The obsessions and increased anxiety reportedly led S. to feel suicidal, with a plan to either shoot herself or jump off a building. S. also had had worsening sleep over the week prior to admission, increased irritability, and loss of interest and pleasure.
S
was a 16-year-old girl with a reported history of major . depressive disorder (MDD), generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), nonverbal learning disability (NVLD), and autism spectrum disorder (ASD). S. was admitted to an acute inpatient psychiatric unit because of worsening intrusive thoughts and active suicidal ideation (SI) with a plan. History of Present Illness
S. had a history of anxiety and depression beginning in childhood. She began to experience the onset of OCD symptoms, including preoccupation with contamination, at the age of 10, and began seeing a therapist at that time. S. then started to experience worsening depressive symptoms, including low mood, increased sleep, poor concentration, and fatigue, and was referred to a psychiatrist who started her on sertraline 75 mg at 12 years of age. There was minimal improvement, and S. was subsequently hospitalized for the first time after an incident of cutting and suicidal ideation. During this 2 week hospitalization, S.’s medication was switched to fluoxetine, which was titrated up to 30 mg. S. was discharged to an intensive short-term acute residential unit, but ultimately re-presented to the inpatient unit after 3 days, because of worsening intrusive thoughts and suicidal ideation while at the residential facility. This second hospitalization lasted 9 days, after which S. stabilized and was discharged back to the community on fluoxetine 40 mg. S. did well for *1 year, but after school ended the following year, she was referred to the emergency department (ED) after 2 weeks of worsening anxiety, depression, and suicidal ideation with a plan. It is of note that S. was no longer experiencing OCD symptoms, but had significant worsening of her anxiety. During this hospitalization, her fluoxetine was increased to 80 mg, and she was discharged in good condition. After this hospitalization, S. underwent psychoeducational testing; additional diagnoses of ASD and nonverbal learning disability were made. S. reportedly did very well in the 3 years between the last admission and her most recent hospitalization; OCD symptoms were well controlled and her depression and anxiety seemed to stabilize. Approximately 9 months prior to the current admission, S. started 1 2 3
Past Psychiatric History S. had been hospitalized three times for anxiety, OCD, and depression as described. S. had a history of prior suicidal ideation without prior attempts.
Department of Psychiatry, New York University School of Medicine, New York, New York. Department of Psychiatry, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
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ADVANCED PEDIATRIC PSYCHOPHARMACOLOGY Developmental History S. was born full term via Cesarean delivery for placenta previa, with a birth weight of 4.8 kg. The pregnancy was characterized by episodes of placental separation with some hemorrhages. S. had speech and fine motor delays requiring early intervention from ages 1 to 3 years. S. was noted to have difficulties interacting with peers from a very young age, and was described as ‘‘socially awkward’’ and a ‘‘loner.’’ S. had stereotypical movements such as rocking back and forth, shaking her torso, and flapping her hands. She also had sensory sensitivities, particularly to sound, which led to exacerbated startle responses. Educational History S. had an individualized education plan (IEP) for social and emotional difficulties. She had just completed grade 10 in a regular education classroom setting. She did well academically, receiving mostly As and Bs. Social History S. lived with her mother, father, and two older siblings, ages 18 and 20 years. She had few friends and was described as ‘‘socially awkward’’ by her mother. She denied any drug or alcohol use, and was not sexually active. There was no history of bullying or abuse. Family History S.’s father and a paternal aunt had been diagnosed with bipolar disorder. Her mother and maternal grandfather had a history of depression. A maternal cousin had been diagnosed with ASD. Medical History S. had polycystic ovarian syndrome (PCOS), for which she takes an oral contraceptive and metformin. She has a history of irregular menstrual cycles. She is overweight with a body mass index (BMI) of 38. There was no history of any major childhood illnesses or surgery. She is up to date on vaccinations. Medication History In addition to her presenting regimen of ziprasidone 40 mg (4 months), bupropion 300 mg (9 months), and lamotrigine 250 mg (6 months), S. had had previous trials of fluoxetine 80 mg (3 years), sertraline 75 mg (2 months), and venlafaxine 112.5 mg (3 months). Venlafaxine, bupropion, and ziprasidone appeared to make her anxiety worse. Sertraline and lamotrigine appeared to be ineffective. Fluoxetine was initially started at 10 mg when she was 12 years of age, and was titrated up to 80 mg over the course of a year, with improvement in her OCD and anxiety-related symptoms, but did not successfully target her depression. Mental Status Examination on Admission to Hospital S. was a tall, overweight adolescent who was adequately groomed. Eye contact was poor. There was no evidence of tremors or tics. S. described her mood as ‘‘not good’’ with an anxious and tearful affect. Her speech was well articulated, but somewhat quiet. Her thought process was tangential with content notable for perseveration regarding obsessions and fears about contamination and about her identity being stolen. She displayed no homicidal ideation, but reported recent suicidal ideation with a plan. She stated that this plan involved general ideas, as she did not identify a specific building she would jump off of, and did not have access to a gun. There was no evidence of active delusions or abnormal perceptions; however, S. did exhibit some paranoid ideation in regard
75 to identity theft. S.’s insight and judgment were significantly limited. Hospital and Treatment Course Upon admission, S. was taking ziprasidone 80 mg, bupropion XL 300 mg, and lamotrigine 250 mg, which had been prescribed and monitored by her outpatient psychiatrist, as described. Initially, S.’s medications were consolidated to focus on her core symptoms of perseverative, intrusive thoughts and agitation. Frequently, S. was observed pacing the hallway, stopping staff and questioning them in order to gain relief from her intrusive thoughts. S. had extreme difficulty maintaining a conversation; she often displayed tangential thinking with an inability to ignore intrusive thoughts. The decision was made to taper S.’s ziprasidone and bupropion because of her worsening anxiety; risperidone 0.25 mg b.i.d. and fluoxetine 10 mg daily were initiated in an attempt to reduce her anxiety and disorganized thinking. However, S. was noted to be awake as many as six times per night, often perseverating on various anxious thoughts and unable to fall back asleep. Specifically, S. became fixated on a concern that everything she touched on the unit had blood on it, and that, therefore, she was at high risk of contracting HIV. She compulsively checked things that she would touch to ensure that there was no blood, and repeatedly asked staff for reassurance. S. did not sleep during the day, and did not indicate feeling more tired than usual despite only sleeping a few hours per night. At the same time, S. did not display grandiosity, psychomotor agitation, pressured speech, or impulsivity. Because of the strong family history of bipolar disorder and worsening sleep disturbance in the context of disorganized thoughts, there was concern that S.’s fluoxetine could be unmasking or worsening an underlying bipolar disorder. Fluoxetine was withheld and risperidone was slowly titrated up to 3 mg at night and 1 mg in the morning to target what was formulated as an underlying bipolar disorder. Although S. showed fewer outward signs of distress (she no longer constantly stopped staff to ask whether a particular object had blood on it), she continued to struggle with intrusive thoughts. She continued to have difficulty maintaining a conversation for longer than a few phrases before devolving into her obsessions. Interestingly, although the frequency of her intrusive thoughts did not seem to be improving, they did shift to becoming increasingly less distressing to S. Initially she perseverated on acquiring HIV from blood, then she started obsessing about accidentally defecating on herself, then about urinating on herself, and, finally, about forgetting to wash her hands. Her sleep did improve somewhat on the risperidone, but she also began to experience daytime tiredness. After *1 week on risperidone with minimal improvement in frequency of her obsessions, the team decided to target S.’s OCD symptoms and anxiety. To that end, fluoxetine 10 mg was reinitiated. After 4 days, S. showed a partial response, and for the first time in months, S. was able to read a book by herself without being interrupted by her obsessions. The fluoxetine was increased to 20 mg, and S. was able to conduct prolonged conversations without needing to interrupt, and to discuss her perseverative worries and thoughts. S. experienced a complete resolution of her disordered sleeping. On the occasional night when she woke, S. was able to quickly fall back asleep. She was subsequently discharged to a day treatment program for ongoing treatment. Brief Formulation In summary, S. was a 16-year-old adolescent girl with a history of PCOS, anxiety, depression, OCD, nonverbal learning disability, and ASD referred to the ED for poorly controlled anxiety and
76 intrusive thoughts, with a suicidal plan. Past history was significant for long-standing, severe anxiety and mood dysregulation, suicidal ideation with a plan, and multiple psychiatric hospitalizations. Additionally, S. had a history of early developmental and social delays, and nonverbal learning disability; all of those have contributed to her cognitive rigidity, limited coping skills and longstanding difficulties with transitions and peer relationships. S.’s anxiety appears to have been well controlled for several years with psychotherapy and fluoxetine, but had worsened in the context of multiple medication changes and psychosocial stressors. Given a family history of bipolar disorder, unipolar depression, and autism, S. had an underlying diathesis for both neurodevelopmental disorders and major affective illness. A further biological factor may have been her medical history of PCOS, which has been associated with a variety of affective disorders. Precipitating factors for her current hospitalization included the end of the school year, a source of important structure for her; the stress of applying for jobs; and the impending transition to young adulthood. That said, S. had many strengths, including strong family support, solid academic performance, and good rapport with her outpatient clinicians. Diagnostic and Statistical Manual for Mental Disorders, 5th ed. (DSM-5) Diagnoses Autism Spectrum Disorder Obsessive Compulsive Disorder Major Depression, past; rule out Bipolar Disorder Additional diagnoses: Specific Learning Disorder (nonverbal learning disability) Discussion The diagnostic dilemma presented by S. centered on deciding optimal treatment for a child displaying hallmarks of both OCD and bipolar disorder. Symptomatically, S. showed evidence of a significant sleep disturbance, and, possibly, decreased need for sleep, as well as disorganized thoughts and obsessions. Her strong genetic predisposition to bipolar disorder was an obfuscating factor. Disentangling these diagnoses was further complicated by her underlying ASD diagnosis. Approximately 70% of children with ASD have a comorbid psychiatric condition (Simonoff et al. 2008) and often present a diagnostic challenge because the impairments in language, emotional processing, and intelligence that are frequently found in individuals with autism can obscure traditional assessment measures (Witwer and Lecavalier 2010). Presentations of comorbid conditions such as anxiety and OCD are often atypical and difficult to distinguish from underlying ASD symptomatology (White and Roberson-Nay 2009). It is unclear to what extent S.’s diagnosis of PCOS played in her presentation, but others have noted links between PCOS and depression, anxiety, and bipolar disorder (Himelein and Thatcher 2006). Population estimates of adolescents identify a prevalence of *3% for OCD (Valleni-Basile et al. 1994), 2.5% for bipolar I or II disorder (Merikangas et al. 2012), and 1.5% for ASD (Autism and Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators 2014). Estimates for OCD comorbidity in children with ASD range from 8% to as high as 37% (Leyfer et al. 2006; Simonoff et al. 2008), whereas bipolar disorder is more rarely comorbid with ASD – * 2% (Leyfer et al. 2006). There is some evidence that there are higher rates of bipolar comorbidity in higher functioning ASD patients, such as S. (Munesue et al. 2008). There is also evidence that bipolar disorder presents earlier in children with ASD than in those without the diagnosis ( Joshi et al. 2013).
ADVANCED PEDIATRIC PSYCHOPHARMACOLOGY Establishment of diagnostic clarity is critical, as the first line treatment for adolescents with bipolar mania includes an atypical antipsychotic agent and mood stabilizer; medications with potentially substantial side effect profiles (McClellan et al. 2007). On the other hand, if a primary diagnosis of OCD is formulated, cognitive behavioral therapy (CBT) is first line for mild to moderate OCD, whereas selective serotonin reuptake inhibitors (SSRIs) are first line for moderate to severe OCD (Geller et al. 2012). The decision to treat a child displaying symptoms suggestive of mania with an SSRI is delicate, as the medication class has been shown to trigger and exacerbate manic, mixed, and rapid cycling episodes (Kowatch et al. 2005). A case series published in 1999 highlighted three children with Asperger’s disorder who were treated with fluoxetine and subsequently developed or had significant worsening symptoms of mania (Damore et al. 1998). Because S. had previously been treated with fluoxetine without major adverse effects, the initial decision to focus on her anxiety and OCD symptoms was prudent. However, when a worsening sleep disturbance became apparent and was coupled with her preexisting disorganized thinking, it became necessary to consider whether S. in fact had bipolar disorder, particularly in the context of her strong genetic predisposition. Decreased need for sleep is a well-known and well-described symptom of bipolar disorder (Geller et al. 2002) but it is nonspecific, as insomnia has been noted as a prominent symptom in a variety of other psychiatric and neurodevelopmental disorders, including depression, anxiety, attention-deficit/hyperactivity disorder (ADHD), ASD, and epilepsy (Nunes and Bruni 2015). Over a 2 year period, 50% of children and adolescents (ages 5–16 years) referred to a sleep center for persistent insomnia had a psychiatric diagnosis (Ivanenko et al. 2004). None of the children in the study was found to have OCD however, and there is less attention focused on sleep disorders in this population. However, there is literature showing clearly that children with OCD have high levels of sleep-related problems, including feeling overtired, experiencing nightmares, and parental reports of ‘‘sleeping less than most kids’’ (Storch et al. 2008), as well as an overall decrease in sleep efficiency and increase in sleep latency (Rapoport et al. 1981). Therefore, it is important that the clinician keep an open mind to differential diagnoses when attempting to uncover a psychiatric cause of sleep disturbance in children. Intrusive thoughts are a hallmark characteristic of OCD. However, just as sleep disturbance can be seen in a wide variety of childhood-onset psychiatric disorders, obsessive thoughts do not necessarily implicate OCD as the diagnosis. Children with autism frequently demonstrate repetitive behaviors that can appear to represent obsessions and compulsions (Baron-Cohen 1989). Adolescents with disordered eating frequently display obsessional traits that often persist in these individuals even after recovery (Bulik 2002). Intrusive thoughts often cause distress among victims of trauma (Dougall et al. 1999). Although investigation is limited into obsessive symptoms in pediatric bipolar disorder, research in adults has found that excessive rumination is highly prevalent in patients with bipolar disorder (Gruber et al. 2008). It is important to consider the possibility of comorbid OCD with bipolar disorder, which can cause significant impairment in adolescent functioning (Masi et al. 2004). Finally, it is notable that intrusive thoughts can lead to significant sleep disturbances (Hall et al. 1997). Although intrusive thoughts and disordered sleep lend themselves to certain diagnoses, there is reason to be judicious when formulating how they contribute to the overall picture of an adolescent’s mental functioning. In S.’s case, the final diagnosis was thought to be OCD, and the decision was made for a retrial of fluoxetine to target anxiety, ruminations, obsessions, and compulsions. S. previously had responded
ADVANCED PEDIATRIC PSYCHOPHARMACOLOGY inadequately to fluoxetine for major depression, but had demonstrated improvement in anxiety symptoms. This is not surprising, as evidence suggests that SSRIs are more efficacious in treatment of anxiety and OCD than depression (Bridge et al. 2007). The decision to reinitiate fluoxetine followed after risperidone (up to 4 mg) had had little demonstrable impact on either S.’s thought distortions or her sleep disturbance. Although her symptoms could be seen as early manifestations of bipolar disorder, despite her genetic predisposition, it was formulated that these symptoms could all be parsimoniously explained by uncontrolled OCD. S.’s insomnia and rumination were not accompanied by grandiosity, pressured speech, increased goaldirected activities, or impulsivity, therefore providing less support for a diagnosis of an acute manic or mixed episode. Future research to facilitate understanding of the complicated manifestations of ASD and disentanglement of the comorbidities is certainly warranted. Acknowledgment We would like to acknowledge and thank Natasha Toralba Kostek and Maxwell Luber for their assistance in review and preparation of the manuscript. Disclosures Philip Cawkwell, Dr. Lawler, and Dr. Maneta have no conflicts of interest or financial ties to disclose. Dr. Coffey has received research support from the American Academy of Child and Adolescent Psychiatry, Astra Zeneca, Auspex/Teva, Catalyst, Eli Lilly, Genco Sciences, Neurocrine, NIMH, Shire, and the Tourette Association of America. References Autism and Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators: Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill Summ 63:1–21, 2014. Baron–Cohen S: Do autistic children have obsessions and compulsions? Br J Clin Psychol 28 ( Pt 3):193–200, 1989. Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent DA: Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: A metaanalysis of randomized controlled trials. JAMA 297:1683–1696, 2007. Bulik CM: Eating disorders in adolescents and young adults. Child Adolesc Psychiatr Clin N Am 11:201–218, 2002. Damore J, Stine J, Brody L: Medication-induced hypomania in Asperger’s disorder. J Am Acad Child Adolesc Psychiatry 37:248–249, 1998. Dougall AL, Craig KJ, Baum A: Assessment of characteristics of intrusive thoughts and their impact on distress among victims of traumatic events. Psychosom Med 61:38–48, 1999. Geller B, Zimerman B, Williams M, Delbello MP, Frazier J, Beringer L: Phenomenology of prepubertal and early adolescent bipolar disorder: Examples of elated mood, grandiose behaviors, decreased need for sleep, racing thoughts and hypersexuality. J Child Adolesc Psychopharmacol 12:3–9, 2002. Geller DA, March J, AACAP Committee on Quality Issues: Practice parameter for the assessment and treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 51:98–113, 2012. Gruber J, Eidelman P, Harvey AG: Transdiagnostic emotion regulation processes in bipolar disorder and insomnia. Behav Res Ther 46:1096–1100, 2008. Hall M, Buysse DJ, Dew MA, Prigerson HG, Kupfer DJ, Reynolds CF, 3rd: Intrusive thoughts and avoidance behaviors are associated
77 with sleep disturbances in bereavement-related depression. Depress Anxiety 6:106–112, 1997. Himelein MJ, Thatcher SS: Polycystic ovary syndrome and mental health: A review. Obstet Gynecol Surv 61:723–732, 2006. Ivanenko A, Barnes ME, Crabtree VM, Gozal D: Psychiatric symptoms in children with insomnia referred to a pediatric sleep medicine center. Sleep Med 5:253–259, 2004. Joshi G, Biederman J, Petty C, Goldin RL, Furtak SL, Wozniak J: Examining the comorbidity of bipolar disorder and autism spectrum disorders: A large controlled analysis of phenotypic and familial correlates in a referred population of youth with bipolar I disorder with and without autism spectrum disorders. J Clin Psychiatry 74:578–586, 2013. Kowatch RA, Fristad M, Birmaher B, Wagner KD, Findling RL, Hellander M: Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 44:213–235, 2005. Leyfer OT, Folstein SE, Bacalman S, Davis NO, Dinh E, Morgan J, Tager–Flusberg H, Lainhart JE: Comorbid psychiatric disorders in children with autism: interview development and rates of disorders. J Autism Dev Disord 36:849–861, 2006. Masi G, Perugi G, Toni C, Millepiedi S, Mucci M, Bertini N, Akiskal HS: Obsessive-compulsive bipolar comorbidity: Focus on children and adolescents. J Affect Disord 78:175–183, 2004. McClellan J, Kowatch R, Findling RL: Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 46:107–125, 2007. Merikangas KR, Cui L, Kattan G, Carlson GA, Youngstrom EA, Angst J: Mania with and without depression in a community sample of US adolescents. Arch Gen Psychiatry 69:943–951, 2012. Munesue T, Ono Y, Mutoh K, Shimoda K, Nakatani H, Kikuchi M: High prevalence of bipolar disorder comorbidity in adolescents and young adults with high-functioning autism spectrum disorder: A preliminary study of 44 outpatients. J Affect Disord 111:170–175, 2008. Nunes ML, Bruni O: Insomnia in childhood and adolescence: Clinical aspects, diagnosis, and therapeutic approach. J Pediatr (Rio J) 91(6 Suppl 1):S26-35, 2015. Rapoport J, Elkins R, Langer DH, Sceery W, Buchsbaum MS, Gillin JC, Murphy DL, Zahn TP, Lake R, Ludlow C, Mendelson W: Childhood obsessive-compulsive disorder. Am J Psychiatry 138:1545–1554, 1981. Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G: Psychiatric disorders in children with autism spectrum disorders: Prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry 47:921–929, 2008. Storch EA, Murphy TK, Lack CW, Geffken GR, Jacob ML, Goodman WK: Sleep-related problems in pediatric obsessive-compulsive disorder. J Anxiety Disord 22:877–885, 2008. Valleni–Basile LA, Garrison CZ, Jackson KL, Waller JL, McKeown RE, Addy CL, Cuffe SP: Frequency of obsessive-compulsive disorder in a community sample of young adolescents. J Am Acad Child Adolesc Psychiatry 33:782–791, 1994. White SW, Roberson–Nay R: Anxiety, social deficits, and loneliness in youth with autism spectrum disorders. J Autism Dev Disord 39:1006–1013, 2009. Witwer A, Lecavalier L: Validity of comorbid psychiatric disorders in youngsters with autism spectrum disorders. J Dev Phys Disabil 22:367–380, 2010.
Address correspondence to: Barbara J. Coffey, MD, MS Icahn School of Medicine at Mount Sinai One Gustave L. Levy Place, Box 1230 New York, New York 10029 E-mail: [email protected]
Advanced Pediatric Psychopharmacology
Staying Up at Night: Overlapping Bipolar and Obsessive-Compulsive Disorder Symptoms in an Adolescent with Autism Spectrum Disorder Presenters: Philip Cawkwell, BA,1 Ashley Lawler, MD,2 and Eleni Maneta, MD2 Discussant: Barbara J. Coffey, MD, MS3
Chief Complaint and Presenting Problem
to report some worsening in her mood again, and her psychiatrist added bupropion extended-release to her fluoxetine. This did not provide adequate relief, and S. was tapered off fluoxetine and started on venlafaxine, which was titrated up to 112.5 mg. S. did well for a few months, but during the winter holiday from school she decompensated, with worsening depression and anxiety. She was subsequently switched from venlafaxine to lamotrigine, because of both family history of bipolar disorder, and increased irritability that had been noted. Cognitive rigidity was also noted at that time, and ziprasidone 40 mg was added as a stabilizing agent. Although these medication changes seemed to improve her depression, the outpatient psychiatrist noted that S.’s anxiety had worsened again. S. and her mother agreed that S. had begun to decompensate rapidly in the 4 weeks prior to this current admission following the end of the school year. S. stated that she felt that she had had to ‘‘grow up’’ and apply for jobs and learn to drive, causing her anxiety to significantly worsen. She stated that she began to experience severe intrusive thoughts. Specifically, S. became fixated on the idea of someone stealing her identity, as she had to give out her social security number when applying for jobs. Although she maintained insight into the small likelihood of this happening, S. experienced increasing levels of distress over these thoughts, which impaired her ability to complete her applications. S. also began to have an increased fixation on germs and cleanliness; that is, excessively washing her hands and seeking reassurance about being clean. S.’s mother reported that in the context of S.’s recent decompensation, ziprasidone was increased to 80 mg daily, which led to worsening agitation and anxiety. The obsessions and increased anxiety reportedly led S. to feel suicidal, with a plan to either shoot herself or jump off a building. S. also had had worsening sleep over the week prior to admission, increased irritability, and loss of interest and pleasure.
S
was a 16-year-old girl with a reported history of major . depressive disorder (MDD), generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), nonverbal learning disability (NVLD), and autism spectrum disorder (ASD). S. was admitted to an acute inpatient psychiatric unit because of worsening intrusive thoughts and active suicidal ideation (SI) with a plan. History of Present Illness
S. had a history of anxiety and depression beginning in childhood. She began to experience the onset of OCD symptoms, including preoccupation with contamination, at the age of 10, and began seeing a therapist at that time. S. then started to experience worsening depressive symptoms, including low mood, increased sleep, poor concentration, and fatigue, and was referred to a psychiatrist who started her on sertraline 75 mg at 12 years of age. There was minimal improvement, and S. was subsequently hospitalized for the first time after an incident of cutting and suicidal ideation. During this 2 week hospitalization, S.’s medication was switched to fluoxetine, which was titrated up to 30 mg. S. was discharged to an intensive short-term acute residential unit, but ultimately re-presented to the inpatient unit after 3 days, because of worsening intrusive thoughts and suicidal ideation while at the residential facility. This second hospitalization lasted 9 days, after which S. stabilized and was discharged back to the community on fluoxetine 40 mg. S. did well for *1 year, but after school ended the following year, she was referred to the emergency department (ED) after 2 weeks of worsening anxiety, depression, and suicidal ideation with a plan. It is of note that S. was no longer experiencing OCD symptoms, but had significant worsening of her anxiety. During this hospitalization, her fluoxetine was increased to 80 mg, and she was discharged in good condition. After this hospitalization, S. underwent psychoeducational testing; additional diagnoses of ASD and nonverbal learning disability were made. S. reportedly did very well in the 3 years between the last admission and her most recent hospitalization; OCD symptoms were well controlled and her depression and anxiety seemed to stabilize. Approximately 9 months prior to the current admission, S. started 1 2 3
Past Psychiatric History S. had been hospitalized three times for anxiety, OCD, and depression as described. S. had a history of prior suicidal ideation without prior attempts.
Department of Psychiatry, New York University School of Medicine, New York, New York. Department of Psychiatry, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
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ADVANCED PEDIATRIC PSYCHOPHARMACOLOGY Developmental History S. was born full term via Cesarean delivery for placenta previa, with a birth weight of 4.8 kg. The pregnancy was characterized by episodes of placental separation with some hemorrhages. S. had speech and fine motor delays requiring early intervention from ages 1 to 3 years. S. was noted to have difficulties interacting with peers from a very young age, and was described as ‘‘socially awkward’’ and a ‘‘loner.’’ S. had stereotypical movements such as rocking back and forth, shaking her torso, and flapping her hands. She also had sensory sensitivities, particularly to sound, which led to exacerbated startle responses. Educational History S. had an individualized education plan (IEP) for social and emotional difficulties. She had just completed grade 10 in a regular education classroom setting. She did well academically, receiving mostly As and Bs. Social History S. lived with her mother, father, and two older siblings, ages 18 and 20 years. She had few friends and was described as ‘‘socially awkward’’ by her mother. She denied any drug or alcohol use, and was not sexually active. There was no history of bullying or abuse. Family History S.’s father and a paternal aunt had been diagnosed with bipolar disorder. Her mother and maternal grandfather had a history of depression. A maternal cousin had been diagnosed with ASD. Medical History S. had polycystic ovarian syndrome (PCOS), for which she takes an oral contraceptive and metformin. She has a history of irregular menstrual cycles. She is overweight with a body mass index (BMI) of 38. There was no history of any major childhood illnesses or surgery. She is up to date on vaccinations. Medication History In addition to her presenting regimen of ziprasidone 40 mg (4 months), bupropion 300 mg (9 months), and lamotrigine 250 mg (6 months), S. had had previous trials of fluoxetine 80 mg (3 years), sertraline 75 mg (2 months), and venlafaxine 112.5 mg (3 months). Venlafaxine, bupropion, and ziprasidone appeared to make her anxiety worse. Sertraline and lamotrigine appeared to be ineffective. Fluoxetine was initially started at 10 mg when she was 12 years of age, and was titrated up to 80 mg over the course of a year, with improvement in her OCD and anxiety-related symptoms, but did not successfully target her depression. Mental Status Examination on Admission to Hospital S. was a tall, overweight adolescent who was adequately groomed. Eye contact was poor. There was no evidence of tremors or tics. S. described her mood as ‘‘not good’’ with an anxious and tearful affect. Her speech was well articulated, but somewhat quiet. Her thought process was tangential with content notable for perseveration regarding obsessions and fears about contamination and about her identity being stolen. She displayed no homicidal ideation, but reported recent suicidal ideation with a plan. She stated that this plan involved general ideas, as she did not identify a specific building she would jump off of, and did not have access to a gun. There was no evidence of active delusions or abnormal perceptions; however, S. did exhibit some paranoid ideation in regard
75 to identity theft. S.’s insight and judgment were significantly limited. Hospital and Treatment Course Upon admission, S. was taking ziprasidone 80 mg, bupropion XL 300 mg, and lamotrigine 250 mg, which had been prescribed and monitored by her outpatient psychiatrist, as described. Initially, S.’s medications were consolidated to focus on her core symptoms of perseverative, intrusive thoughts and agitation. Frequently, S. was observed pacing the hallway, stopping staff and questioning them in order to gain relief from her intrusive thoughts. S. had extreme difficulty maintaining a conversation; she often displayed tangential thinking with an inability to ignore intrusive thoughts. The decision was made to taper S.’s ziprasidone and bupropion because of her worsening anxiety; risperidone 0.25 mg b.i.d. and fluoxetine 10 mg daily were initiated in an attempt to reduce her anxiety and disorganized thinking. However, S. was noted to be awake as many as six times per night, often perseverating on various anxious thoughts and unable to fall back asleep. Specifically, S. became fixated on a concern that everything she touched on the unit had blood on it, and that, therefore, she was at high risk of contracting HIV. She compulsively checked things that she would touch to ensure that there was no blood, and repeatedly asked staff for reassurance. S. did not sleep during the day, and did not indicate feeling more tired than usual despite only sleeping a few hours per night. At the same time, S. did not display grandiosity, psychomotor agitation, pressured speech, or impulsivity. Because of the strong family history of bipolar disorder and worsening sleep disturbance in the context of disorganized thoughts, there was concern that S.’s fluoxetine could be unmasking or worsening an underlying bipolar disorder. Fluoxetine was withheld and risperidone was slowly titrated up to 3 mg at night and 1 mg in the morning to target what was formulated as an underlying bipolar disorder. Although S. showed fewer outward signs of distress (she no longer constantly stopped staff to ask whether a particular object had blood on it), she continued to struggle with intrusive thoughts. She continued to have difficulty maintaining a conversation for longer than a few phrases before devolving into her obsessions. Interestingly, although the frequency of her intrusive thoughts did not seem to be improving, they did shift to becoming increasingly less distressing to S. Initially she perseverated on acquiring HIV from blood, then she started obsessing about accidentally defecating on herself, then about urinating on herself, and, finally, about forgetting to wash her hands. Her sleep did improve somewhat on the risperidone, but she also began to experience daytime tiredness. After *1 week on risperidone with minimal improvement in frequency of her obsessions, the team decided to target S.’s OCD symptoms and anxiety. To that end, fluoxetine 10 mg was reinitiated. After 4 days, S. showed a partial response, and for the first time in months, S. was able to read a book by herself without being interrupted by her obsessions. The fluoxetine was increased to 20 mg, and S. was able to conduct prolonged conversations without needing to interrupt, and to discuss her perseverative worries and thoughts. S. experienced a complete resolution of her disordered sleeping. On the occasional night when she woke, S. was able to quickly fall back asleep. She was subsequently discharged to a day treatment program for ongoing treatment. Brief Formulation In summary, S. was a 16-year-old adolescent girl with a history of PCOS, anxiety, depression, OCD, nonverbal learning disability, and ASD referred to the ED for poorly controlled anxiety and
76 intrusive thoughts, with a suicidal plan. Past history was significant for long-standing, severe anxiety and mood dysregulation, suicidal ideation with a plan, and multiple psychiatric hospitalizations. Additionally, S. had a history of early developmental and social delays, and nonverbal learning disability; all of those have contributed to her cognitive rigidity, limited coping skills and longstanding difficulties with transitions and peer relationships. S.’s anxiety appears to have been well controlled for several years with psychotherapy and fluoxetine, but had worsened in the context of multiple medication changes and psychosocial stressors. Given a family history of bipolar disorder, unipolar depression, and autism, S. had an underlying diathesis for both neurodevelopmental disorders and major affective illness. A further biological factor may have been her medical history of PCOS, which has been associated with a variety of affective disorders. Precipitating factors for her current hospitalization included the end of the school year, a source of important structure for her; the stress of applying for jobs; and the impending transition to young adulthood. That said, S. had many strengths, including strong family support, solid academic performance, and good rapport with her outpatient clinicians. Diagnostic and Statistical Manual for Mental Disorders, 5th ed. (DSM-5) Diagnoses Autism Spectrum Disorder Obsessive Compulsive Disorder Major Depression, past; rule out Bipolar Disorder Additional diagnoses: Specific Learning Disorder (nonverbal learning disability) Discussion The diagnostic dilemma presented by S. centered on deciding optimal treatment for a child displaying hallmarks of both OCD and bipolar disorder. Symptomatically, S. showed evidence of a significant sleep disturbance, and, possibly, decreased need for sleep, as well as disorganized thoughts and obsessions. Her strong genetic predisposition to bipolar disorder was an obfuscating factor. Disentangling these diagnoses was further complicated by her underlying ASD diagnosis. Approximately 70% of children with ASD have a comorbid psychiatric condition (Simonoff et al. 2008) and often present a diagnostic challenge because the impairments in language, emotional processing, and intelligence that are frequently found in individuals with autism can obscure traditional assessment measures (Witwer and Lecavalier 2010). Presentations of comorbid conditions such as anxiety and OCD are often atypical and difficult to distinguish from underlying ASD symptomatology (White and Roberson-Nay 2009). It is unclear to what extent S.’s diagnosis of PCOS played in her presentation, but others have noted links between PCOS and depression, anxiety, and bipolar disorder (Himelein and Thatcher 2006). Population estimates of adolescents identify a prevalence of *3% for OCD (Valleni-Basile et al. 1994), 2.5% for bipolar I or II disorder (Merikangas et al. 2012), and 1.5% for ASD (Autism and Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators 2014). Estimates for OCD comorbidity in children with ASD range from 8% to as high as 37% (Leyfer et al. 2006; Simonoff et al. 2008), whereas bipolar disorder is more rarely comorbid with ASD – * 2% (Leyfer et al. 2006). There is some evidence that there are higher rates of bipolar comorbidity in higher functioning ASD patients, such as S. (Munesue et al. 2008). There is also evidence that bipolar disorder presents earlier in children with ASD than in those without the diagnosis ( Joshi et al. 2013).
ADVANCED PEDIATRIC PSYCHOPHARMACOLOGY Establishment of diagnostic clarity is critical, as the first line treatment for adolescents with bipolar mania includes an atypical antipsychotic agent and mood stabilizer; medications with potentially substantial side effect profiles (McClellan et al. 2007). On the other hand, if a primary diagnosis of OCD is formulated, cognitive behavioral therapy (CBT) is first line for mild to moderate OCD, whereas selective serotonin reuptake inhibitors (SSRIs) are first line for moderate to severe OCD (Geller et al. 2012). The decision to treat a child displaying symptoms suggestive of mania with an SSRI is delicate, as the medication class has been shown to trigger and exacerbate manic, mixed, and rapid cycling episodes (Kowatch et al. 2005). A case series published in 1999 highlighted three children with Asperger’s disorder who were treated with fluoxetine and subsequently developed or had significant worsening symptoms of mania (Damore et al. 1998). Because S. had previously been treated with fluoxetine without major adverse effects, the initial decision to focus on her anxiety and OCD symptoms was prudent. However, when a worsening sleep disturbance became apparent and was coupled with her preexisting disorganized thinking, it became necessary to consider whether S. in fact had bipolar disorder, particularly in the context of her strong genetic predisposition. Decreased need for sleep is a well-known and well-described symptom of bipolar disorder (Geller et al. 2002) but it is nonspecific, as insomnia has been noted as a prominent symptom in a variety of other psychiatric and neurodevelopmental disorders, including depression, anxiety, attention-deficit/hyperactivity disorder (ADHD), ASD, and epilepsy (Nunes and Bruni 2015). Over a 2 year period, 50% of children and adolescents (ages 5–16 years) referred to a sleep center for persistent insomnia had a psychiatric diagnosis (Ivanenko et al. 2004). None of the children in the study was found to have OCD however, and there is less attention focused on sleep disorders in this population. However, there is literature showing clearly that children with OCD have high levels of sleep-related problems, including feeling overtired, experiencing nightmares, and parental reports of ‘‘sleeping less than most kids’’ (Storch et al. 2008), as well as an overall decrease in sleep efficiency and increase in sleep latency (Rapoport et al. 1981). Therefore, it is important that the clinician keep an open mind to differential diagnoses when attempting to uncover a psychiatric cause of sleep disturbance in children. Intrusive thoughts are a hallmark characteristic of OCD. However, just as sleep disturbance can be seen in a wide variety of childhood-onset psychiatric disorders, obsessive thoughts do not necessarily implicate OCD as the diagnosis. Children with autism frequently demonstrate repetitive behaviors that can appear to represent obsessions and compulsions (Baron-Cohen 1989). Adolescents with disordered eating frequently display obsessional traits that often persist in these individuals even after recovery (Bulik 2002). Intrusive thoughts often cause distress among victims of trauma (Dougall et al. 1999). Although investigation is limited into obsessive symptoms in pediatric bipolar disorder, research in adults has found that excessive rumination is highly prevalent in patients with bipolar disorder (Gruber et al. 2008). It is important to consider the possibility of comorbid OCD with bipolar disorder, which can cause significant impairment in adolescent functioning (Masi et al. 2004). Finally, it is notable that intrusive thoughts can lead to significant sleep disturbances (Hall et al. 1997). Although intrusive thoughts and disordered sleep lend themselves to certain diagnoses, there is reason to be judicious when formulating how they contribute to the overall picture of an adolescent’s mental functioning. In S.’s case, the final diagnosis was thought to be OCD, and the decision was made for a retrial of fluoxetine to target anxiety, ruminations, obsessions, and compulsions. S. previously had responded
ADVANCED PEDIATRIC PSYCHOPHARMACOLOGY inadequately to fluoxetine for major depression, but had demonstrated improvement in anxiety symptoms. This is not surprising, as evidence suggests that SSRIs are more efficacious in treatment of anxiety and OCD than depression (Bridge et al. 2007). The decision to reinitiate fluoxetine followed after risperidone (up to 4 mg) had had little demonstrable impact on either S.’s thought distortions or her sleep disturbance. Although her symptoms could be seen as early manifestations of bipolar disorder, despite her genetic predisposition, it was formulated that these symptoms could all be parsimoniously explained by uncontrolled OCD. S.’s insomnia and rumination were not accompanied by grandiosity, pressured speech, increased goaldirected activities, or impulsivity, therefore providing less support for a diagnosis of an acute manic or mixed episode. Future research to facilitate understanding of the complicated manifestations of ASD and disentanglement of the comorbidities is certainly warranted. Acknowledgment We would like to acknowledge and thank Natasha Toralba Kostek and Maxwell Luber for their assistance in review and preparation of the manuscript. Disclosures Philip Cawkwell, Dr. Lawler, and Dr. Maneta have no conflicts of interest or financial ties to disclose. Dr. Coffey has received research support from the American Academy of Child and Adolescent Psychiatry, Astra Zeneca, Auspex/Teva, Catalyst, Eli Lilly, Genco Sciences, Neurocrine, NIMH, Shire, and the Tourette Association of America. References Autism and Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators: Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill Summ 63:1–21, 2014. Baron–Cohen S: Do autistic children have obsessions and compulsions? Br J Clin Psychol 28 ( Pt 3):193–200, 1989. Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent DA: Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: A metaanalysis of randomized controlled trials. JAMA 297:1683–1696, 2007. Bulik CM: Eating disorders in adolescents and young adults. Child Adolesc Psychiatr Clin N Am 11:201–218, 2002. Damore J, Stine J, Brody L: Medication-induced hypomania in Asperger’s disorder. J Am Acad Child Adolesc Psychiatry 37:248–249, 1998. Dougall AL, Craig KJ, Baum A: Assessment of characteristics of intrusive thoughts and their impact on distress among victims of traumatic events. Psychosom Med 61:38–48, 1999. Geller B, Zimerman B, Williams M, Delbello MP, Frazier J, Beringer L: Phenomenology of prepubertal and early adolescent bipolar disorder: Examples of elated mood, grandiose behaviors, decreased need for sleep, racing thoughts and hypersexuality. J Child Adolesc Psychopharmacol 12:3–9, 2002. Geller DA, March J, AACAP Committee on Quality Issues: Practice parameter for the assessment and treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 51:98–113, 2012. Gruber J, Eidelman P, Harvey AG: Transdiagnostic emotion regulation processes in bipolar disorder and insomnia. Behav Res Ther 46:1096–1100, 2008. Hall M, Buysse DJ, Dew MA, Prigerson HG, Kupfer DJ, Reynolds CF, 3rd: Intrusive thoughts and avoidance behaviors are associated
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Address correspondence to: Barbara J. Coffey, MD, MS Icahn School of Medicine at Mount Sinai One Gustave L. Levy Place, Box 1230 New York, New York 10029 E-mail: [email protected]
