October 9, 2007

Asperger Syndrome and Medication Treatment

By Tsai, Luke Y

Asperger syndrome (AS) is a neurobiological disorder whose core clinical symptoms include impairment in social interaction, impairments in verbal and nonverbal communication, and restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. AS is often accompanied by coexisting neuropsychiatric disorders, including anxiety disorder, affective disorder, obsessive- compulsive disorder, Tourette syndrome, attention-deficit/ hyperactivity disorder, and sleep disorders. These clinical features provide the rationale for the use of psychotropic medications (psychopharmacotherapy) in individuals with AS. This article describes the clinical indications for psychopharmacotherapy and provides guidelines for monitoring the effectiveness of medication treatment and for preventing and monitoring the development of side effects and/or adverse effects of psychotropic medications. Editors' Note: This article was solicited for the Focus 22(2) special series on Asperger Syndrome, guest edited by Brenda Smith Myles and Sheila Smith, but appears here due to space limitations in the previous issue.

Behavioral and biological studies have generated evidence to suggest neurobiologic etiologies of Asperger syndrome (AS). At present, however, no specific biological marker or markers have been identified as causing AS. Hence, no treatment modality specifically based on cause has been developed to "cure" individuals with AS. Nevertheless, there is potential for some medications to be helpful in ameliorating psychiatric or behavioral symptoms that can interfere with an individual's ability to participate in educational, social, work, and family systems, as well as to enhance positive responses to other forms of intervention in persons with AS.

Many of the behavioral problems or disturbed emotions reported may be clinical manifestations of coexisting neuropsychiatric disorders or side effects induced by psychotherapeutic medications. Strong data have shown that psychotherapeutic medications can be quite effective as first-line treatments for certain neuropsychiatric disorders that may develop in individuals with AS. These neuropsychiatric disorders include attention-deficit/ hyperactivity disorder (ADHD), obsessivecompulsive disorder (OCD), tic disorders, affective disorder, anxiety disorder, seizure disorders, and sleep disorders. The psychopharmacological field has also compiled knowledge of side effects that may be produced by these medications.

Early detection and effective treatment of these coexisting neuropsychiatric disorders or medication-induced side effects are critical. Like most medications, psychotherapeutic agents can correct or compensate for some malfunctions in the human body or systems. They do not cure AS, but they can lessen the challenges to persons with AS and their family members and improve patients' quality of life.

This article was written to summarize the current state of knowledge of when and how medication can be used as part of a comprehensive treatment of individuals with AS. Building on an overview of the comorbid neuropsychiatrie disorders of AS, the article outlines a process of medical assessment of these disorders and concludes with guidelines for psychopharmacological treatment. These recommendations are developed mainly from the author's experience with persons with AS, as well as from limited published clinical studies.

Comorbid Neuropsychiatric Disorders of AS

Information about comorbid neuropsychiatric disorders of AS is limited because professionals in the United States have only recognized AS as a distinct clinical entity for a relatively short time. Furthermore, there is no established method for clinicians to assess comorbid neuropsychiatrie disorders in this population. Nonetheless, AS has been associated with reported cases of other psychiatric disorders, such as Tourette syndrome (Berthier, Bayes, & Tolosa, 1993; Kadesjo & Gillberg, 2000; Marriage et al., 1993; Ringman & Jankovic, 2000; Searcy et al., 2000), ADHD (Ghaziuddin & Butler, 1998), affective illness or mood disorders (Duggal, 2001; Frazier, Doyle, Chiu, & Coyle, 2002; Ghaziuddin & Butler, 1998; Tantam, 1988, 1991; Wing, 1981), anxiety disorder (Tantam, 1991), OCD (Tantam, 1991), and schizophrenia (Tantam, 1991).

Green, Gilchrist, Burton, and Cox (2000) examined psychiatric and social functioning in 20 individuals with AS ages 11 to 19 years with full-scale IQ scores above 70. The researchers found that 35% of the adolescents met the criteria outlined in The ICD-10 Classification of Mental and Behavioral Disorders (World Health Organization, 1992) for generalized anxiety disorder, 10% met the criteria for a specific phobia, and 30% had two or more additional psychiatric diagnoses. Further, the children and adolescents with AS had significantly more symptoms of worry, hypochondria, panic, specific fears, and obsessive ruminations and rituals than the control group with a diagnosis of conduct disorder. Mental status exams also revealed more physical signs of anxiety, nonfacial tics, and unusual emotional responsiveness in the AS group. Another study found that rates of some comorbid disorders were higher for individuals with AS than for the individuals with autism (Klin, Pauls, Schultz, & Volkmar, 2005).

Polimeni, Richdale, and Francis (2005) asked parents of 66 typically developing (TD) children, 53 children with autism, and 52 children with AS to complete a survey on their children's sleep patterns, the nature and severity of any sleep problems, and the success of any treatment attempted. The results showed a high prevalence of sleep problems, with significantly more problems reported in the autism and AS groups (TD = 50%, autism = 73%, AS = 73%); however, there were no significant differences between the autism and AS groups on severity or type of sleep problem. Children with AS were significantly more likely to be sluggish and disoriented after waking and had higher total scores on the Behavioral Evaluation of Disorders of Sleep (Schreck, Mulick, & Rojahn, 2003) than did the children in the other two groups.

When viewing autistic disorder and AS as autism spectrum disorders (ASD), some clinicians have cited anxiety as a common feature (Attwood, 1998; Tantam, 2000). Kim, Szatmari, Bryson, Streiner, and Wilson (2000) examined the prevalence of anxiety and mood problems in a sample of 59 children with autism and AS with IQ scores above the cutoff for mental retardation. The researchers found that 14% of the children in the study scored at least two standard deviations above the mean on a parent-report measure of generalized anxiety and on the internalizing factor, which includes generalized anxiety, separation anxiety, and depression.

Allik, Larsson, and Smedje (2006) compared the sleep and associated behavioral characteristics of thirty-two 8- to 12year- old children with Asperger syndrome or high-functioning autism (AS/ HFA) with those of an equal number of age- and gender-matched typically developing children. Several aspects of sleep-wake behavior, including insomnia, were surveyed using a structured pediatric sleep questionnaire in which parents reported their children's sleep patterns for the previous 6 months. Recent sleep patterns were monitored by use of a 1-week sleep diary and actigraphy. (Actigraphy is a method of activity and sleep study in which a small actigraph unit is mounted on a participant for an extended period of time. The unit, which typically includes an accelerometer, continually records the participant's movements. When the data are transferred to a computer, they can be analyzed and used in the study of the participant's sleep patterns.) Behavioral characteristics were surveyed by use of information gleaned from parent and teacher answers to questions on the High-Functioning Autism Spectrum Screening Questionnaire (Ehlers, Gillberg, & Wing, 1999) and the Strengths and Difficulties Questionnaire (Goodman, 2001). Parent-reported difficulties in initiating sleep and daytime sleepiness were more common in children with AS/HFA than in controls, and 10 of the 32 children with AS/HFA (31%), but none of the controls, fulfilled the study definition of pediatric insomnia. Parent-reported cases of insomnia corresponded to the findings obtained of the actigraphic study.

Little is known about the risk of psychiatric disorders in adults with AS. In a follow-up study of 85 adults with Asperger syndrome, Tantam (1991 ) reported that 30 (35%) met the criteria set forth in the ninth revision of the International Classification of Diseases (World Health Organization, 1977) for a psychiatric disorder rather than a developmental disorder. Tantarn noted that the proportion observed in his study was likely higher than what would be found in an unselected community sample, as psychiatric disorder was one factor leading to psychiatric referral and thus to participation in the study. Nevertheless, there was a higher-than-expected risk of psychosis, with mania (occurring in 9.0% of participants) being more common than schizophrenia (3.5%). The single most common disorder was depression, which occurred in 15.0% of the subjects. Anxiety disorder was also common, reaching clinically significant severity in 7.0% of the cases; it is often associated with depression in this study. Tani et al. (2003) compared 20 adults with AS who were not using medication with 10 healthy controls who did not have any neuropsychiatrie disorders. The structured psychiatric interview for Axis I and II disorders (common psychiatric disorders, and mental retardations and personality disorders, respectively) listed in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994) were given to both groups, as were the Beck Depression Inventory (Beck, 1961) and the Wechsler Adult Intelligence Scale-Revised (Wechsler, 1981), a commonly used measure for assessment of cognitive functions. Sleep quality was assessed with a questionnaire asking for the quality of sleep during 6 consecutive days and a description of possible sleep problems in the participants' own words. Compared with controls and with normative values of what constitutes good sleep, the adults with AS had frequent insomnia. There was a substantial psychiatric comorbidity with only four participants with AS devoid of other Axis I or II disorders. Also, these persons displayed insomnia. The authors concluded that the neuropsychiatrie deficits inherent in AS predispose individuals both to insomnia and to anxiety and mood disorders.

Howlin (2000) reviewed the issue of comorbid disorders and noted that little is known about outcomes for individuals with AS. She concluded, "More research into psychiatric conditions in adulthood is badly needed, not only to identify the true level of risk, but also to improve knowledge amongst clinicians about how psychiatric disorders in this group are manifested" (p. 76).

Problems With Diagnosis of Comorbid Neuropsychiatrie Disorders of AS

Individuals with AS present a diverse clinical picture, which often makes diagnosis and treatment difficult. One factor that leads to confusion for clinicians making diagnostic and programming decisions is the wide variability of characteristics within AS. Thus, it is difficult for most clinicians without adequate experience with individuals with AS to determine whether symptoms are due to a separate comorbid disorder or related to the underlying AS. Furthermore, the DSM-IV diagnostic criteria for many psychiatric disorders require a subjective description of experience. Hence, many clinicians are reluctant to make additional psychiatric diagnoses in young children with AS who are incapable of providing diagnostic information via interviews or patient self-report scales. Even older children or adolescents with AS may not know whether their symptoms are due to comorbid neuropsychiatrie disorders or to AS itself. Thus, they usually do not report or complain about their symptoms.

At present, the validity of self-reporting for individuals with AS has not been established. There is also no "gold standard" for determining the validity of a diagnostic instrument in assessing comorbid neuropsychiatrie disorders in this population. These problems interfere with identification and understanding of comorbid disorders. As a result, comorbid neuropsychiatric disorders have often been misdiagnosed or unrecognized in individuals with AS. The presence of comorbid neuropsychiatrie disorders can create great difficulties and stress in an individual's life because the comorbid disorders can be debilitating. Further, caregivers usually experience additional stress when their children develop comorbid neuropsychiatric disorders. Therefore, it is crucial that caregivers learn about early recognition of comorbid neuropsychiatrie disorders in their children with ASD to ensure early and effective treatment.

Medication Treatment Based on a Functional Behavioral Analysis

Given the current lack of a reliable and valid assessment protocol, it is crucial that a complete functional behavioral analysis be carried out by a qualified and experienced professional (usually a psychologist or a behavioral therapist) before a patient is referred to a physician for consideration of medication treatment. While a functional behavioral analysis does not confirm a diagnosis of comorbid neuropsychiatrie disorders, it may be able to prevent an unnecessary medical referral by identifying conditions or symptoms that are learned and appear as maladaptive behavior. Such behaviors usually do not respond to psychotherapeutic medications but can be managed or improved by using nonmedical interventions such as behavioral therapy, educational intervention, and problem- solving skill training.

The results from the functional behavioral analysis should be presented at a follow-up meeting of the team (consisting of the student of concern, his/her parents or legal guardians and other caregivers). A decision to refer a patient for further medical assessment is appropriate when the team members agree that the collected data indicate that the behaviors or symptoms of concern may not be solely the result of environmental cues or consequences.

General Approach to Medication Treatment

To achieve effective medication treatment in individuals with ASD, it is essential to learn about the basic principles of psycho- pharmacotherapy, the work-ups for use of various medications, the indications and contraindications of each medication, the measurement of medication effects, and the prevention, recognition, and management of medication-induced side effects.

Basic Principles of Psychopharmacotherapy

1. Selection of appropriate medication requires comprehensive information about the individual being assessed, including current functioning, family history, and medical history. It is crucial that parents or caregivers maintain up-to-date medical records, because the prescribing physician will need to know whether the individual being treated has seizures, has previously used any medication (and if so, what his or her response was), or is currendy taking any medication. Many medications may lower the threshold for seizures or interact with anticonvulsants either to enhance or to diminish their effectiveness.

2. Medication treatment must be based upon a sound diagnosis of the presenting symptoms or behaviors and a rational choice of a specific medication (e.g., use of Haldol to treat motor and/or vocal tics in patients with Tourette syndrome).

3. The use of medication should always be considered as part of a comprehensive intervention, as described above. Without additional therapies, the improvement associated with the medication usually disappears after the medication is discontinued.

4. The individual with AS should be involved in the treatment process as much as possible given his or her age and level of functioning. Every effort should be made to help the individual understand the reason and purpose for taking the medication or medications and the possible side effects. Sensitive counseling can help overcome any fears of taking medication that the individual may have. This approach will prevent the development of a negative attitude or misperception toward the use of the medications.

5. Parents and other caregivers should always be included in the process. They need to be informed about the reasons for medication therapy, the likely therapeutic effects, possible side effects, and so on. Parents or caregivers are a critical resource for monitoring the child's compliance with taking medication, as well as a necessary source of information about the child's therapeutic response to the medication and the development of any side effects.

6. During the initial phases of medication therapy, the individual with AS should be seen at least once a week by the physician. Once the problems have been stabilized (usually after several weeks), a medication maintenance program can begin. At that point, the individual can be seen less frequently (monthly or bimonthly, for example) to review therapeutic response and development of side effects.

7. Placebo effects (beneficial effects arising from the act of giving medication rather than the medication itself) often exist and should be weighed carefully to determine continuation of the medication. The individual taking the medication, family members, caregivers, and even the prescribing physician can produce the placebo effect. Therapeutic gains need to be weighed carefully against side effects, and all efforts must be made to minimize risks to the individual.

8. In general, if an individual does not respond to a medication within 4 weeks while in the therapeutic range, when the individual is already at the highest dosage of a medication as recommended by the literature, it is unlikely that he or she will respond at a later date. In cases with therapeutic response, medication treatment should proceed at optimal dosage for a period of 4 to 6 months. The medication should then be discontinued for at least a 1- to 2-month "medication holiday" to permit evaluation of the need for continued treatment as well as assessment of the development of side effects such as growth changes or movement disorders.

Baseline Medical Assessment

An effective medication treatment begins with a thorough medical assessment, including a comprehensive physical and neurological examination; intensive speech, language, and cognitive assessments; and, in specific cases, extensive neurophysiological, neurochemical, and neuroimaging assessments. The pretreatment assessment is essential for detecting medical conditions such as seizure disorder, meningitis, lead poisoning, brain tumors, endocrinological disorders, and chromosomal abnormalities that can cause or exacerbate problems. Pretreatment assessment is also essential for establishing the patient's baseline physical, psychological, behavioral, and cognitive status prior to medication treatment, as well as for monitoring both the effectiveness of and any adverse reactions to medication treatment.

Helpful Questions

The individual with AS and his or her legal guardian should have the right and be given the choice to decline medication therapy. The diagnosing physician should provide information about other nonmedication therapies such as cognitivebehavioral therapy (CBT) and other psychosocial treatments. To help individuals with AS and their caregivers gain a better understanding of how medication is used to address comorbid disorders, the prescribing physician should make sure to address the following frequently asked questions:

1 . What medications are typically used to treat the disorder or disorders in question?

2. How do the medications work in the human body?

3. How should the medications be taken?

4. How can one tell if the medication is working?

5 . What should the individual or his or her caregivers do if the individual develops side effects?

6. How long will it take for the medication to work?

7. Can the medication be used with other medications, including over-the-counter medicines for common illnesses?

8. How frequently should the physician see the individual, and for how long will the individual need to take the medicine?

Evidence-Based Medication Treatment of Comorbid Neuropsychiatric Disorders of AS

Empirical studies of medication treatment of AS and comorbid neuropsychiatric disorders are scarce. A literature search using the Entrez PubMed database for the keywords Asperger syndrome or Asperger disorder and medication treatment yielded only a few publications. Some of them were case reports; others were studies of small samples that combined participants with autistic disorder and those with AS into a single group.

Furusho et al. (2001 ) reported that an 8-year-old boy with AS could not sleep due to recalling his awful experiences while crying every night, and he refused to go to school. He was treated with fluvoxamine, a selective serotonin reuptake inhibitor, at the dose of 25 mg daily. Four weeks after the treatment, his repetitive behavior and hyperactivity decreased, and his night crying diminished. Although he still had difficulties in communicating with other persons, he was able to attend extracurricular classes in a private school.

Frazier et al. (2002) reported on a 13 1/2 -year-old boy with diagnoses of AS and bipolar disorder (mixed, with psychotic features). He had a long history of aggression and unsafe behaviors. After treatment for many years with various psychotropic medications without success, the authors finally found that a combination of 1 mg twice a day of oral clonazepam, 2,100 mg per day of lithium, and 3 mg per day of risperidone led to a marked reduction in his behavioral symptoms. Later his mood normalized and his aggressive, extremely compulsive and disruptive behaviors stopped.

Staller (2003) reported that a 34-year-old man with lifelong, disabling AS and a 20-year history of failed psychotherapeutic and pharmacologic interventions was prescribed aripiprazole. This led to dramatic symptomatic improvement, including improved sociability; increased self-awareness; reduced rigidity, anxiety, and irritability; and reduced preoccupation with circumscribed esoteric interests.

Hollander, Dolgoff- Kaspar, Cartwright, Rawitt, and Novotny (2001) carried out a retrospective pilot study to determine whether divalproex sodium was effective in treating core dimensions and associated features of autism. Fourteen patients who met the DSM-IV criteria for autism, AS, or pervasive developmental disorder-not otherwise specified (PDDNOS), including those with and without a history of seizure disorders or electroencephalogram abnormalities, were treated with divalproex sodium. Of the 14 patients who completed a trial of divalproex sodium, 10 (71%) were rated as having a sustained response to treatment. The mean dose of divalproex sodium was 768 mg/day (range = 125-2,500 mg/day), and it was generally well tolerated. Improvement was noted in core symptoms of autism and associated features of affective instability, impulsivity, and aggression.

Hollander et al. (2003) examined the impact of oxytocin on repetitive behaviors in 15 adults with autism or AS via randomized double-blind oxytocin and placebo challenges. The primary outcome measure was an instrument that rated six repetitive behaviors: need to know, repeating, ordering, need to tell or ask, self-injury, and touching. Patients with ASD showed a significant reduction in repetitive behaviors following oxytocin infusion in comparison to placebo infusion.

Namerow, Thomas, Bostic, Prince, and Monuteaux (2003) assessed the effectiveness and tolerability of the selective serotonin reuptake inhibitor Citalopram in the treatment of patients with pervasive developmental disorders (PDDs). The medical charts of 15 children and adolescents (ages 6-16 years) with Asperger syndrome, autism, or PDD-NOS treated with Citalopram were retrospectively reviewed. The final dose of Citalopram was 16.9 +- 12.1 mg/day, with a treatment duration of 218.8 +- 167.2 days. Independent ratings on the Clinical Global Impression Severity and Improvement Scales (CGI Scale; NIMH, 1985) allowed comparison between baseline and posttreatment PDD symptoms at the last visit. Eleven adolescents (73%) exhibited significant improvement in PDD, anxiety, or mood score (z - 2.95, p - .003). Anxiety symptoms associated with PDDs improved significantly in 66% of patients (z = 2.83, p = .005), and mood symptoms improved significantly in 47% (z = 2.78, ? = .005). Mild side effects were reported by five patients (33%). The authors concluded that the data suggest Citalopram may be effective, safe, and well tolerated as part of the treatment of PDDs.

Posey, Puntney, Sasher, Kern, and McDougle (2004) used open- label guanfacine to treat 80 study participants with PDDs (10 females and 70 males, ages 3-18 years). It was found that treatment with guanfacine (0.25-9.00 mg/day for 7-1,776 days) was effective in 19 of 80 (24%) the participants. Participants with PDD-NOS (11 of 28 responders, or 39%) and AS (2 of 6 responders, or 33%) showed a greater rate of global response than did participants with autistic disorder (6 of 46 responders, or 13%). Further, there was a trend for participants without comorbid mental retardation (9 of 24, or 38%) to respond at a greater rate than participants with mental retardation (10 of 56 subjects, or 18%). Symptom improvement was seen in hyperactivity, inattention, insomnia, and tics. Guanfacine was well tolerated and did not lead to significant changes in blood pressure or heart rate.

Rausch et al. (2005) studied 13 male patients ages 6 to 18 years who had been diagnosed with AS according to DSM-IV criteria and were enrolled in a 12-week, prospective, openlabel pilot study. All of the participants were started on risperidone at 0.25 mg twice a day. Doses were increased based on clinical indication and tolerability. The primary efficacy variable was the Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1982). Each participant's baseline score served as his control. Secondary efficacy measures included the Positive and Negative Syndrome Scale (Kay, Fiszbein, & Opler, 1987), the Brief Psychiatric Rating Scale (Overall & Gorham, 1962), the Montgomery-Asberg Depression Rating Scale (Montgomery & Asberg, 1979), the Global Assessment Scale (Endicott, Spitzer, Fleiss, & Cohen, 1976), and a modified Asperger Syndrome Diagnostic Scale (Myles, Bock, & Simpson, 2000). A statistically significant improvement was noted from baseline for last-observation-carried- forward analyses as well as for analyses of 12-week completers (w = 9) in the primary outcome measure, SANS scores. Statistically significant improvement was also found in all secondary efficacy measurements.

Mathai, Bourne, and Cranswick (2005) reported lessons learned in conducting a clinical drug trial of sertralin in 12 children with AS. However, the results of the study itself have not been published.

The findings from these published studies must be interpreted with caution, given that there are many methodological problems (e.g., small sample size, open-label or retrospective studies, lack of control trials). It thus is not clear how generalizable these data are to the entire population of individuals with AS.

Suggestions for Medical Treatment of Individuals With AS

The review of the literature included little evidence-based information about pharmacological treatments of individuals with Asperger syndrome. Nevertheless, this author has successfully used stimulants (e.g., Ritalin), antidepressants (e.g., Prozac), and medications for anxiety disorder (e.g., BuSpar), OCD (e.g., Luvox), Tourette syndrome (e.g., Haldol), and sleep disorders (e.g., Desyrel) in treating these conditions in children with AS. At the same time, however, older adolescents and adults with AS and comorbid mental conditions refused to accept the diagnostic conclusion and would not cooperate with any professionals' interventions, including medications.

The following clinical conditions in individuals with AS are potentially responsive to drugs. In some of the conditions, the administration of certain drugs is based on well-documented research into other psychiatric disorders without comorbid AS. Because little research has been done on the use of medication to treat these disorders with comorbid AS, the following suggestions are based on the limited clinical and empirical experiences of the present author and a few other investigators.

Individuals With Anxiety Disorders and Related Conditions

Generalized Anxiety Disorder. Ideally, in treatment of acute anxiety, the medication chosen should be of the lowest possible dose for the shortest possible time. Dosages should be flexible rather than arbitrary, and should be taken intermittendy at a time of increased symptoms rather than on a fixed daily schedule. In general, 1 to 7 days of medication treatment are recommended for a reaction to an acute situational stress; however, 1 to 6 weeks of treatment may be needed for short-term anxiety due to specific life events. Acute Anxiety Episode, Mild

1. Start with cognitive behavior therapy (CBT) in higher functioning older adolescents and adults.

2. If nonresponse or insufficient response, add a benzodiazepine (BZD).

3. If nonresponse or insufficient response, add BuSpar (buspirone).

Acute Anxiety Episode, Moderate to Severe

1. Start with a BZD plus CBT (in higher functioning older adolescents and adults).

2. If nonresponse or insufficient response, add BuSpar.

Chronic Anxiety With Prior BZD Treatment

1. Add BuSpar, then reduce and eliminate BZD.

Chronic Anxiety Without Prior BZD

1 . Start with BuSpar.

2. If nonresponse or insufficient response, add a BZD.

3. If nonresponse or insufficient response, reduce and eliminate BZD or BuSpar and add an antidepressant (AD; tricyclic antidepressant [TCA] or selective serotonin reuptake inhibitor [SSRI]).

4. If response is insufficient, add an SSRI (e.g., Anafranil [clomipramine], Prozac [fluoxetine], Luvox [fluvoxamine], Zoloft [sertraline], or Paxil [paroxetine].

Maintenance or Prophylaxis Treatment of Generalized Anxiety Disorder. Maintenance therapy refers to therapy undertaken to prevent a relapse. Prophylaxis refers to the prevention of recurrent episodes. Prophylaxis involves indefinite continuation of medication, usually over many years. Particularly if the episodes have short prodromes (i.e., subclinical symptoms before the onset of an episode) or develop insidiously, continuous prophylactic therapy would be more appropriate.

Clinical judgment plays a major role in the decision to continue anxiolytic treatment beyond 4 to 6 weeks. Although long-term administration may maintain initial improvement, it is unlikely to result in further gains. However, the chronic nature of anxiety disorders and the frequency of eventual relapse after treatment discontinuation suggest that in some individuals long-term treatment may be indicated.

Periodic reassessment of the efficacy, safety, and necessity of long-term anxiolytic therapy is critical because the high rate of comorbidity of generalized anxiety disorder witii other psychiatric disorders suggests that an alternative approach (such as adding an antidepressant while reducing and eliminating an anxiolytic drug) may be more appropriate in certain individuals.

Panic Attacks, Mild

1 . Start with behavior therapy.

2. If response is insufficient, add an SSRI or a TCA.

3. If response is still insufficient, add Xanax (alprazolam) or Klonopin (clonazepam).

Panic Attacks, Moderate

1. Start with a TCA or an SSRI, plus behavior therapy.

2. If response is insufficient, add Xanax or Klonopin.

Panic Attacks, Severe

1. Start with a TCA or an SSRI, plus Xanax or Klonopin, and behavior therapy.

2. If response is still insufficient, add Depakote (sodium valproate and valproic acid) with or without a BZD.

Social Phobia

1 . Start with behavior therapy.

2. If response is still insufficient, add Xanax or Catapres (Clonidine).

Specific Phobia

1. Start with behavior therapy (systematic desensitization).

2. If response is insufficient, add Inderal (propranolol).

Individuals With Obsessive-Compulsive Disorder (OCD) and Related Conditions

OCD, Mild Symptoms

1 . Start with behavior therapy.

2. If response is insufficient, add an SSRI or clomipramine (in individuals with a history of or current seizure disorder, Anafranil should be the last choice).

3. If response is still insufficient, try other SSRIs in sequence.

OCD, Moderate to Severe Symptoms

1. Start with an SSRI plus behavior therapy.

2. If response is insufficient, use sequential trials of other SSRIs or Anafranil (Anafranil should be the last choice in individuals with a history of or current seizure disorder).

3. If response is still insufficient, add BuSpar or Klonopin.

Maintenance Medication Therapy for OCD. Clinical evidence clearly indicates that most individuals relapse if SSRIs are discontinued. Therefore, treatment should be continued and eventually tapered as follows:

1. Continue the effective medication for 6 months.

2. Taper the dose gradually till symptoms reemerge.

3. Go back up to the dose being taken right before the symptoms reemerged, then continue therapy indefinitely, with follow-up by the prescribing physician every 2 to 3 months.

Individuals With Mood Disorders

It is still not clear whether ultracyclical bipolar mood disorder is a part of AS or if it should be considered as a different type of mood disorder. At the present, it tends not to respond well to available mood stabilizers, such as Depakote, Zyprexa (danzapine), Risperdal, and Tegretol (carbamazepine).

Major Depressive Disorder, Mild to Moderate, Single or Recurrent

1. Start with one of the following:

* SSRI, Effexor (venlafaxine), nefazodone, or Remeron (mirtazapine)

* Antidepressant previously effective in the individual or a family member

* Heterocyclic antidepressant, preferably a secondary amine TCA, if side effects are tolerated

2. If response is partial, combine with lithium, thyroid supplement, or pindolol.

3. If the response is insufficient, use two different anti- depressants concurrently (e.g., add an SSRI slowly to a TCA).

4. If psychosis emerges, add an antipsychotic (e.g., Haldol [haloperidol] or Risperdal [risperidone]).

5. If the response is still insufficient, add electroconvulsive therapy (ECT).

Major Depressive Disorder With Marked Anxiety, Panic Attacks, or Agitation

1. Start with a BZD plus an antidepressant (not nefazodone).

2. If the response is insufficient, switch class of antidepressant (e.g., Norpramin [a heterocyclic antidepressant] to Paxil [an SSRI]).

3. If response is insufficient, add an antidepressant of another class (e.g., Wellbutrin [bupropion], an aminoketone).

4. If response is insufficient, add a mood stabilizer (e.g., Depakote).

5. If psychosis emerges, add an antipsychotic (e.g., Haldol or Risperdal).

6. If response is still insufficient, add ECT

Bipolar Depressive Disorder

1. Start with an antidepressant plus a mood stabilizer.

2. If response is partial, combine with lithium, thyroid supplement, or pindolol.

3. If the response is still insufficient, use two different antidepressants concurrently (e.g., add an SSRI slowly to a TCA).

4. If psychosis emerges, add an antipsychotic (e.g., Haldol or Risperdal).

5. If response is still insufficient, add ECT

Severe or Medication Nonresponse Depression

1. Start with ECT.

Maintenance or Prophylactic Therapy of Depressive Disorders. Maintenance therapy is mandatory following successful induction of a remission. Maintenance therapy should be continued for 6 to 12 months after an acute depressive episode. After 12 months, medications can usually be reduced and eliminated over a period of several weeks to avoid autonomic rebound or SSRI discontinuation syndrome. If symptoms reemerge, medication should be reinstated and maintained for an additional 3 to 6 months before an attempt is made to taper it again. Prophylaxis refers to the prevention of recurrent episodes. Prophylaxis involves indefinite continuation of medication, usually over many years. In particular, if the episodes have short prodromes (i.e., subclinical symptoms before the onset of an episode) or develop insidiously, continuous prophylactic therapy would be more appropriate. In individuals with recurrent severe unipolar depressions and a high risk of suicide, indefinite prophylactic antidepressants with the least adverse effects may be required.

Manic Episode With Mild to Moderate Symptoms

1. Start with Depakote or lithium. Add thyroid supplement if thyroid-stimulating hormone (TSH) is elevated.

2. If the response is still insufficient, add an antipsychotic.

3. If response is still insufficient and there is immediate danger, discontinue lithium and add ECT.

Manic Episode With Moderate to Severe Symptoms and/or Psychotic Symptoms

1. Start with an antipsychotic plus Depakote or lithium.

2. If response is insufficient, add a BZD; add thyroid supplement if TSH is elevated.

3. If response is still insufficient and there is immediate danger, discontinue lithium and add ECT

Manic Episode in Rapid Cycle, Mixed States, or Prior Nonresponse to Lithium

1. Start with Depakote with or without a BZD or an antipsychotic.

2. If response is insufficient, switch to Tegretol with or without a BZD or an antipsychotic.

3. If response is still insufficient, use Tegretol plus Depakote with or without a BZD or an antipsychotic.

4. If response is still insufficient and there is immediate danger, add ECT.

Maintenance or Prophylaxis Therapies for Manic Episodes. The majority of individuals with bipolar disorder have one or more recurrences; therefore, it is critically important to develop effective and safe long-term treatments. Individuals who respond to lithium or Depakote should continue the medication for 1 to 2 years, and the prescribing physician should follow up every 2 to 3 months. The individual should slowly taper off the medication over several weeks. If a relapse occurs, he or she should resume the medication for and indefinite length of therapy, and the prescribing physician should follow up every 2 to 3 months

Persons With ADHD

Many individuals may have attentional problems due to lack of motivation but are misdiagnosed as having an ADHD. These misdiagnosed individuals usually do not respond to medication treatment. Appropriate behavioral and educational interventions would be more effective in these individuals. The following recommendations are for those individuals who have DSM-IV diagnosis of ADHD.

Individuals With Other Neurological Disorders

1. Begin with Sfrattera (atomoxetine) or a TCA.

2. If nonresponse or insufficient response, use sequential trials with other TCAs, Wellbutrin, and Natrexon for inattention, impulsiveness, and hyperactivity or sequential trials with Catapres, Tenex (guanfacine), and Haldol for hyperactivity and impulsiveness.

Higher Functioning Individuals Without Other Neurological Disorders1. Begin with one of the stimulants (e.g., Ritalin, Concerta [methylphenidate], Dexedrine [dextroamphetamine], or Adderall [amphetamine]). 2. If nonresponse or insufficient response, use sequential trials with Ritalin, Concerta, Dexedrine, or Adderall.

4. If still nonresponse or insufficient response, use sequential trials with Strattera, TCAs, Wellbutrin, Natrexon, Catapres, and Tenex.

Individuals With Tic-Like Symptoms or Tic Disorders, Including Tourette Syndrome

The severity of symptoms varies across individuals, and only children and adults whose relationships, performance, and selfesteem are impaired should be considered for medication.

1. Start with Haldol.

2. If nonresponse or insufficient response, switch to Orap (pimozide).

3. If nonresponse or insufficient response, switch to Catapres.

4. If nonresponse or insufficient response, use one of the above medications and add an SSRI.

5. If nonresponse or insufficient response, use sequential trials with other SSRIs.

6. If still nonresponse or insufficient response, switch to either Risperdal or calcium channel blockers, such as verapamil and nifedipine.

Individuals With Unusual Sleeping Patterns

Some children and adolescents with AS develop unusual sleeping patterns. Some children develop completely reversed sleep patterns; that is, they sleep during the day and are awake during the night. Some problems may relate to watching television, listening to music, or reading. The key to solving such problems is to reverse the sleep cycle through a well-planned regimen and change of behaviors. Some children with AS seem to need much more time to settle down for sleep (i.e., have initial insomnia) and/or need less sleep than most typical children. These children tend to keep the whole family awake because of their sleep disturbances. Melatonin may be considered first. Some children respond to antihistamines, such as Benadryl, or medications such as Vistaril or Atarax (hydroxyzine), or Catapres. In other, more severe cases, antidepressants, such as Tofranil (Imipramine) or Desyrel (trazodone), may be considered.

Individuals With AS Who Develop Psychotic Symptoms

Haldol is sometimes the drug of choice. Other antipsychotic medications (e.g., Navane [thiothixenehal], Clozaril [cloza- pine], Zyprexa, Risperdal, Seroquel [quetiapine], Geodone [ziprasidone], or Abilify [aripiprazole] may also be considered.

People With AS Who Become Aggressive and Physically Attack Others

Some of the aggressive behaviors may relate to frustrations of these individuals. They are of great concern because of their devastating effect.

Aggressive and/or Destructive Behaviors Secondary to Coping Difficulties

1 . Start with behavior therapy.

2. If response is insufficient, add Catapres.

3. If response is still insufficient, switch to Prozac or Paxil (at as low a dose as possible).

Aggressive and/or Destructive Behaviors Due to Being Stopped From Doing Things the Person Likes

1. Start with low dose of an SSRI plus behavior therapy.

2. If response is insufficient, sequential trials of other SSRIs.

3. If response is still insufficient, add small dose of Risperdal.

Aggressive and/or Destructive Behaviors Due to Mood Disorder

1. Start with Depakote or lithium.

2. If response is insufficient, add a BZD. Add thyroid supplement if TSH is elevated.

3. If the response is insufficient, add an antipsychotic.

4. If response is still insufficient and there is immediate danger, discontinue lithium and add ECT.

Aggressive and/or Destructive Behaviors for No Apparent Reason

1. Start with Catapres plus behavior therapy.

2. If response is insufficient, add an SSRI.

3. If response is insufficient, use sequential trials of other SSRIs.

4. If response is still insufficient, use sequential trials of Haldol, Risperdal, Desyrel, Depakote, Inderal, a BZD, or lithium.

Measure of Medication Effects

Like any other type of medication, psychotherapeutic medications do not produce the same effects in everyone. Some patients respond better to one medication than to another. Some need larger dosages than others. Age, sex, body size, body chemistry, habits, and diet can all influence a medication's effect. To determine the optimal dosage, many researchers and clinicians prefer to titrate dosage for each patient; that is, to start with a low dosage and then raise it by standardized increments every 3 to 5 days until the optimal clinical effect is seen, a therapeutic range is reached, or side effects begin to interfere with desired changes. Others prefer to employ standardized doses based on the subject's body weight. In addition, certain medications can be measured in the blood to guide their clinical use.

Dosage regulation of any medication depends on reliable measurement of changes or improvements to targeted behaviors. However, in most cases of ASD, patients are unable to report their symptoms or their response to treatment accurately. Furthermore, a positive treatment effect may be a decrease in the frequency or severity of a longstanding behavior or symptom, and this change may not be readily apparent in the clinician's office. Therefore, measurement of treatment response must be done with objective techniques that are reliable (i.e., repeatable over time or across observers) and valid (i.e., reflect what is actually being measured). Various measurement techniques may be employed, including direct behavioral observations, behavioral rating scales, self- reports, standardized tests, learning and performance measures, mechanical movement monitors, and global impression.

In monitoring medication effects, it is important that a decision on adjusting the dosage or changing to another medication be made based on data and information obtained from as many sources as possible. Such an approach can help to avoid problems caused by a biased informant as well as by the placebo effect.

Recognition of Side Effects Caused by Medication Therapy

Recognizing and managing the side effects of psychotherapeutic medications is crucial to ensure optimal use of the medications. Side effects may range from a minor nuisance to a potentially fatal reaction. If unrecognized, medication- induced side effects can affect patient outcome adversely, in terms of both medical and psychiatric well-being. This is particularly true in individuals with AS who, because of their cognitive and communication disabilities, may not be able to comprehend or recognize side effects and hence may be incapable of alerting or informing their caregivers. They may become frightened or suspicious if a sudden change or dysfunction occurs following the administration of medication, and such feelings may trigger tantrums or interfere with compliance. All caregivers of patients who are incapable of reporting side effects should learn how to recognize potential side effects. They should regularly review and assess the emergence of any side effects.

Prevention of Side Effects

The best approach to managing adverse effects is prevention. The following are general guidelines for avoiding possible side effects:

* Begin treatment with one medication.

* Avoid giving the same medication that caused previous side effects in the individual.

* Avoid giving preventive anti-side effect medication, such as antiparkinsonian agents.

* If an individual does not respond to the medication of first choice, discontinue it gradually while a second medication is instituted and its dosage is increased.

* Use the lowest possible maintenance doses once the therapeutic effect has been established.

* Regularly monitor the blood level of the medication (if the therapeutic range of the medication is available) as well as blood counts, blood pressure, pulse rate, electrocardiogram, liver function, height, and weight.

* Regularly perform a complete physical and neurological examination, and monitor side effects using published side-effects rating scales.

* Give drug holidays at least once every 4 to 6 months.

* In most cases, when discontinuing a drug, taper and withdraw it gradually.

Standardized and user-friendly rating scales for monitoring the various medication-induced side effects in individuals with AS have not been developed. However, there are a number of general and specialized rating scales (Connor & Meltzer, 2006) may be used to monitor the development of medication-induced side effects.


Persons with AS are treated with psychotherapeutic medications for maladaptive behaviors that may develop during the course of their lives as well as for symptoms that may be caused by underlying or coexisting neurpsychiatric disorders. However, the use of medications in this population is viewed only as one component of a comprehensive treatment plan for persons with AS. Some existing clinical data have suggested that with an appropriate evaluation, premedication workups, a specific diagnosis, and multiple measures of outcome, pharmacotherapy is a safe and efficacious treatment for some symptoms and comorbid neuropsychiatrie disorders in persons with AS. The evidence-based treatments presented in this article, however, are rather weak. A great deal of work remains to be done. Future research should also place emphasis on studying the efficacy of combined treatments such as pharmacotherapy plus behavioral or psychosocial therapy.


Allik, H., Larsson, J. O., & Smedje, H. (2006). Insomnia in school-age children with Asperger syndrome or high-functioning autism. BMC Psychiatry, 6, 18.

American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: Author.

Andreasen, N. C. (1982). Negative symptoms in schizophrenia. Archives of General Psychiatry, 39, 784-788.

Attwood,T. (1998). Asperger's syndrome: Aguide for parents and professionals. Philadelphia: Kingsley.

Beck, A. T. (1961). Beck depression inventory. Philadelphia: Center for Cognitive Therapy.

Berthier, M. L., Bayes, A., & Tolosa, E. S. (1993). Magnetic resonance imaging in patients with concurrent Tourette's disorder and Asperger's syndrome. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 633-639. Connor, D.F., & Meltzer, B. M. (2006). Practical tools for the clinical child and adolescent psychopharmacologist. In D. F. Connor & B. M. Meltzer (Eds), Pediatric psychopharmacology fast facts (pp. 537-575). New York: W. W. Norton.

Duggal, H. S. (2001). Mood stabilizers in Asperger's syndrome [Letter]. The Australian and New Zealand Journal of Psychiatry, 35, 390-391.

Ehlers, S., Gillberg, C, & Wing, L. (1999). A screening questionnaire for Asperger syndrome and other high-functioning autism spectrum disorders in school age children. Journal of Autism and Developmental Disorders, 29, 129-141.

Endicott, J., Spitzer, R. L., Fleiss, J. L., & Cohen, J. (1976). The global assessment scale: A product for measuring overall severity of psychiatric disturbance. Archives of General Psychiatry, 33, 766-771.

Frazier, J. A., Doyle, R., Chiu, S., & Coyle, J. T. (2002). Treating a child with Asperger's disorder and comorbid bipolar disorder. The American Journal of Psychiatry, 159, 13-21.

Furusho, J., Matsuzaki, K., Ichihashi, I., Satoh, H., Yamaguchi, K., & Kumagai, K. (2001). Alleviation of sleep disturbance and repetitive behavior by a selective serotonin re-uptake inhibitor in a boy with Asperger's syndrome. Brain & Development, 23, 135-137.

Ghaziuddin, M., & Butler, E. (1998). Clumsiness in autism and Asperger syndrome: A further report. Journal of Intellectural Disability Research, 42(Pt. 1), 43-48.

Goodman, R. (2001). Psychometric properties of the strengths and difficulties questionnaire. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 1337-1345.

Green, J., Gilchrist, A., Burton, D., & Cox, A. (2000). Social and psychiatric functioning in adolescents with Asperger syndrome compared with conduct disorder. Journal of Autism and Developmental Disorders, 30, 279-293.

Hollander, E., Dolgoff-Kaspar, R., Cartwright, C, Rawitt, R., & Novotny, S. (2001). An open trial of divalproex sodium in autism spectrum disorders. The Journal of Clinical Psychiatry, 62, 530- 534.

Hollander, E., Novotny, S., Hanratty, M., Yaffe, R, DeCaria, C. M., Aronowitz, B. R, et al. (2003). Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger's disorders. Neuropsychopharmacology, 28, 193-198.

Howlin, P. (2000). Autism and intellectual disability: Diagnostic and treatment issues. Journal of the Royal Society of Medicine, 93, 351-355.

Kadesjo, B., & Gillberg, C. (2000). Tourette's disorder: Epidemiology and comorbidity in primary school children. Journal of the American Academy of Child and Adolescent Psychiatry, 39, 548- 555.

Kay, S. R., Fiszbein, A., & Opler, L. A. (1987). The positive and negative syndrome scale for schizophrenia. Schizophrenia Bulletin, 13, 261-276.

Kam, J. A., Szatmari, P., Bryson, S. E., Streiner, D. L., & Wilson, F. J. (2000). The prevalence of anxiety and mood problems among children with autism and Asperger syndrome. Autism, 4, 117- 132.

Klin, A., Pauls, D., Schultz, R, & Volkmar, F. (2005). Three diagnostic approaches to Asperger syndrome: Implications for research. Journal of Autism and Developmental Disorders, 35, 221- 234.

Marriage, K., Miles, T, Stokes, D., & Davey, M. (1993). Clinical and research implication of the co-occurrence of Asperger's and Tourette syndromes. The Australian and New Zealand Journal of Psychiatry, 27, 666-672.

Mathai, J., Bourne, A., & Cranswick, N. (2005). Lessons learnt in conducting a clinical drug trial in children with Asperger syndrome. Australasian Psychiatry, 13, 173-175.

Montgomery, S. A., & Asberg, M. (1979). A new depression scale designed to be sensitive to change. The British Journal of Psychiatry, 134, 382-389.

Myles, B. S., Bock, S. J., & Simpson, R. L. (2000). Asperger's syndrome diagnostic scale. Austin, TX: PRO-ED.

Namerow, L. B., Thomas, P., Bostic, J. Q., Prince, J., & Monuteaux, M. C. (2003). Use of Citalopram in pervasive developmental disorders. Journal of Developmental and Behavioral Pediatrics, 24, 104-108.

National Institute of Mental Health. (1985). CGI (clinical global impression) scale. Psychopharmacology Bulletin, 21, 839-843.

Overall, J. E., & Gorham, D. R. (1962). The brief psychiatric rating scale. Psychological Reports, 10, 799-812.

Polimeni, M. A., Richdale, A. L., & Francis, A. J. (2005). A survey of sleep problems in autism, Asperger's disorder and typically developing children. Journal of Intellectural Disability Research, 4P(Pt. 4), 260-268.

Posey, D. J., Puntney, J. I., Sasher, T. M., Kem, D. L., & McDougle, C. J. (2004). Guanfacine treatment of hyperactivity and inattention in pervasive developmental disorders: A retrospective analysis of 80 cases. Journal of Child and Adolescent Psychopharmacology, 4, 233-241.

Rausch, J. L., Sirota, E. L., Londino, D. L., Johnson, M. E., Carr, B. M., Bhatia, R., et al. (2005). Open-label risperidone for Asperger's disorder: Negative symptom spectrum response. The Journal of Clinical Psychiatry, 66, 1592-1597.

Ringman, J. M., & Jankovic, J. (2000). Occurrence of tics in Asperger's syndrome and autistic disorder. Journal of Child Neurology, 15, 394-400.

Schreck, K. A., Mulick, J. A., & Rojahn, J. (2003). Development of the behavioral evaluation of disorders of sleep scale. Journal of Child and Family Studies, 12, 349-359.

Searcy, E., Burd, L., Kerbeshian, J., Stenehjem, A., & Franceschini, LA. (2000). Asperger's syndrome, X-linked mental retardation (MRX23), and chronic vocal tic disorder. Journal of Child Neurology, 15, 699-702.

Staller, J. A. (2003). Aripiprazole in an adult with Asperger disorder. Annal of Pharmacotherapy, 37, 1628-1631.

Tani, P., Lindberg, N., Nieminen-von Wendt, T, von Wendt, L., Alanko, L., Appelberg, B., et al. (2003). Insomnia is a frequent finding in adults with Asperger syndrome. BMC Psychiatry, 16(3), 12.

Tantam, D. (1988). Asperger's syndrome. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 29, 245-255.

Tantam, D. (1991). Asperger syndrome in adulthood. In U. Frith (Ed.), Autism and Asperger syndrome (pp. 147-183). Cambridge, England: Cambridge University Press.

Tantam, D. (2000). Psychological disorder in adolescents and adults with Asperger syndrome. Autism, 4, 47-62.

Wing, L. (1981). Asperger's syndrome: A clinical account. Psychological Medicine, 11, 115-129.

Wechsler, D. (1981). Wechsler adult intelligence scale (Rev. ed.). San Antonio, TX: Psychological Corp.

World Health Organization. (1977). International classification of diseases (9th rev. ed.). Geneva, Switzerland: Author.

World Health Organization. (1992). The ICD-10 classification of mental and behavioral disorders: Clinical descriptions and diagnostic guidelines. Geneva, Switzerland: Author.


Luke Y Tsai, MD, is a professor of psychiatry and pediatrics at the University of Michigan Medical School and a research scientist at the University of Michigan College of Literature, Science and Arts. His current interests include diagnosis and classification of pervasive developmental disorders and psychopharmacology in developmental disorders. Address: Luke Y Tsai, University of Michigan Depression Center, Department of Psychiatry, Child and Adolescent Section, Rachel Upjohn Building, 4250 Plymouth Road, Ann Arbor, MI 48105, e-mail: [email protected]

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