Jay A. Salpekar, M.D., Peter Daniolos, M.D., The George Washington University School of Medicine
Very few studies have investigated the characteristics and treatment of individuals with Bipolar Disorder comorbid with Autism Spectrum Disorders (Autism, Aspergers Syndrome, and Pervasive Developmental Disorder). Both conditions are independently associated with a high degree of morbidity; combined they represent some of the most challenging clinical conditions faced by clinicians and caregivers. Challenges exist not only in differentiating psychiatric symptoms from characteristics of the developmental disorder but also in the identification of effective treatment strategies.
Autism Spectrum Disorders (ASD) are characterized by significant impairment in communication, and social interaction, and are associated with stereotyped, repetitive, and idiosyncratic behaviors, interests, and activities. Psychiatric comorbidity is often present, particularly disruptive behavior disorders and learning disorders. Many large-scale research studies of bipolar disorder exclude ASD patients for methodological reasons. Symptoms such as irritable mood, aggression, increased physical activity level, and affective lability may be inappropriately viewed as constitutive elements of ASD, and thus limit identification of bipolar disorder in this population.
Only in recent decades has it become well-accepted that persons with intellectual and/or developmental disability (IDD) could suffer from affective disorders. A sophisticated review twenty years ago reviewed 25 studies and sought to apply DSM-III standard criteria to persons with IDD in order to assess whether affective disorders in general could be identified (Sovner & Hurley, 1983). In individuals with mild and moderate mental retardation, affective disorder diagnoses were effectively made by using standard DSM-III criteria (Sovner & Hurley, 1983). For those with severe and profound mental retardation, the diagnostic criteria were less effective, although changes in vegetative functioning, and positive family history led to clinical suspicion of affective illness (Sovner & Hurley, 1983).
A recent retrospective review of adults with intellectual disability followed up these findings and revealed that applying DSM-IV criteria could also reliably yield identification of bipolar disorder (Cain et al., 2003). Bipolar patients had significantly increased mood and non-mood related symptoms as opposed to patients with other mood disorders (Cain et al., 2003). Bipolar subtypes including rapid-cycling have also been reported, furthering the notion that bipolar disorders may be very prevalent in the IDD population (King, Fay, & Croghan, 2000).
Increased interest in bipolar disorder in the IDD population has led to consensus guidelines being recently developed to address the clinical needs that this population presents. Consensus treatment approaches for bipolar disorder in the IDD population were similar to those in the non-IDD population.
Recently, efforts have been made to describe syndromes within the bipolar disorder spectrum such as explosive mood disorder or outer-directed irritability in child and adolescent populations (Donovan et al., 2000). It is becoming more widely considered that aggressive and disruptive behavior in this population may reflect underlying mood disorder or bipolar disorder (Wozniak et al., 1997). As definitions of bipolar disorder continue to be modified, particularly with an emphasis upon irritability as sufficient mood disruption to meet criteria for bipolar disorder, more persons with IDD are being considered as having bipolar disorder, especially in terms of selecting appropriate treatment (Leibenluft, Charney, Towbin, Bhangoo, & Pine 2003).
Medications commonly categorized as mood stabilizers have gained prominence for the IDD population as the phenotypic similarity between bipolar spectrum disorder and clinically significant symptoms in IDD converge. Such efforts have been applied to the ASD and other populations with an emphasis upon aggression, self-injurious behavior and irritability as specific symptom targets for medication. Such an approach has proven effective in prospective treatment studies using several medications. Several studies suggest effective use of risperidone for aggression (McCracken et al., 2002; Shea et al., 2004; McDougle et al., 2005). Divalproex sodium was effective in targeting impulsivity and affective instability in an open trial (Hollander, Dolgoff-Kaspar, Cartwright, Rawitt & Novotny, 2001), and effective in reducing aggression and irritability in a controlled study (Donovan et al., 2000). There have also been a few case reports showing efficacy in the use of lithium for the treatment of bipolar disorder symptoms in individuals with autistic disorder (Kerbeshian, Burd, & Fisher, 1987; Steingard & Biederman, 1987). However, focused treatment studies directed to comorbid bipolar disorder and ASD are quite rare.
We conducted a retrospective chart review to assess the co-occurrence of autism spectrum disorders and disorders within the bipolar spectrum, and to discover symptom profiles and medications commonly used in these persons. We hypothesized that the presence of Bipolar I disorder would be associated with a higher number of medications used. We also sought to assess clinical outcomes based upon specific medication usage, and ultimately to raise awareness of treatment strategies for this population.
A retrospective chart review was conducted in a tertiary care major metropolitan pediatric facility. Clinical information in all cases was recorded in medical records on a prospective basis for purposes of clinical care. Cases of interest were identified by selecting individual records with primary or secondary ICD diagnosis codes in both mood disorder and autism spectrum disorders. Diagnoses of interest included Autistic Disorder or Pervasive Developmental Disorder, Bipolar Disorder, Bipolar Disorder Not Otherwise Specified, and Mood Disorder Not Otherwise Specified.
Two mental health clinicians experienced with treatment of pervasive developmental disorder patients independently reviewed identified cases. Cases were excluded if insufficient documentation was present that could yield a consensus regarding psychiatric diagnoses. DSM-IV criteria were used to confirm Autism Spectrum Disorders (ASD), Bipolar I Disorder (BPD), and Mood Disorder Not Otherwise Specified (MOOD) diagnoses. Criteria for Manic Episode, required for identification of Bipolar I Disorder are listed in table 1.
Insert as Table 1
DSM-IV Criteria for Manic Episode (DSM-IV-TR) American Psychiatric Association, 2000)
A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary).
During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:
Inflated self-esteem or grandiosity
Decreased need for sleep (e.g., feels rested after only 3 hours of sleep)
More talkative than usual or pressure to keep talking
Flight of ideas or subjective experience that thoughts are racing
Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli)
Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation
Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
The symptoms do not meet criteria for a Mixed Episode.
The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.
The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatments) or a general medical condition (e.g., hyperthyroidism).
(End table 1)
Medication treatment trials were specified as those being prescribed upon initial or follow-up psychiatric phases of treatment. Clinical Global Impression-Improvement (CGI-I) ratings were assessed for bipolar mood disorder target symptoms in each identified course of medication treatment (Guy, 1976). CGI-I ratings were done by mental health clinicians blind to the others ratings. Improvement was deemed to have occurred if CGI-I ratings were 1, 2, or 3 (1-7 scale), based on stabilization of mood disorder symptoms occurring during an identified treatment trial. This project was undertaken with the approval of the in-house Institutional Review Board and Office of Human Subjects Research Protection. Abbott Laboratories, Inc. provided unrestricted research support via an investigator-initiated proposal.
Forty-one individuals met strict inclusion criteria; 22 patients (average age 11.2 years, 20 male, two female) had Bipolar I Disorder, and 19 patients (average age 11.7 years, 18 male, 1 female) had Mood Disorder Not Otherwise Specified. Common symptoms in both groups included impulsivity, psychomotor agitation, distractibility, and explosive rage outbursts.
The most common classes of medications used in the sample were antipsychotics (34), anticonvulsants (23), lithium carbonate (9), antidepressants (15), and stimulants (20). Persons with Bipolar I Disorder were taking an average of 3.1 psychiatric medications and patients with Mood Disorder Not Otherwise Specified were taking an average of 2.7 medications. Treatment trials identified targeted for bipolar disorder symptoms most often included antipsychotics, anticonvulsants, and lithium carbonate. 48 treatment trials yielded improvement while 12 did not show clinical improvement in bipolar or mood disorder symptoms.
The most common medications used in treatment trials included risperidone (9/11 improved), divalproex sodium (8/10 improved), and lithium carbonate (8/9 improved). Other medications used less commonly but also yielding improvement in bipolar symptoms included olanzapine, quetiapine fumarate, aripiprazole, ziprasidone, oxcarbazepine, topiramate, Prolixin, OROS methylphenidate, and mixed amphetamine salts extended release.
Clinical assessment and treatment of children and adolescents with Autism Spectrum Disorder and comorbidity of either Bipolar I disorder or Mood Disorder Not Otherwise Specified is complex. Bipolar spectrum disorder symptoms were widespread in this sample of children and adolescents with autism spectrum disorder regardless of the presence of mood disorder meeting strict criteria for Bipolar I disorder. Both groups had many medication trials and polytherapy was nearly always the case. Bipolar I Disorder was associated with a trend towards both an increased number of medication trials attempted, and slightly more medications used. Atypical antipsychotics, anticonvulsants and lithium were used most commonly and were usually used in combination. Many medications were effective in this sample; however, divalproex sodium, lithium carbonate, and risperidone were used most commonly and with few exceptions, were associated with clinical improvement.
This population is severely ill and reflects possible compounding morbidity from two challenging clinical conditions. It is also possible that bipolar spectrum disorders are underdiagnosed in individuals with autism spectrum disorders. Prospective treatment trials and clearer identification of diagnostic issues are necessary to provide definitive evidence to meet the clinical needs of individuals with Autism Spectrum Disorders.
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