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Introduction
Since the beginning of psychopharmacology, individuals with intellectual disabilities (ID) have been treated with medications (King, 2007). Psychopharmacological practice in persons with ID has been complicated by three different but overlapping approaches:
1. Use of psychotropic medication to address challenging behaviors.
2. Use of psychotropic medication to treat co-occurring psychiatric disorders.
3. Use of medications, some with psychotropic properties, to address ID syndromes themselves, with hope of directly or indirectly addressing associated psychiatric and/or behavioral disorders.
Surrounding this complexity, many individuals with ID and their families, as well as clinicians and researchers, believe that psychotropics, and particularly antipsychotic medications, have been over-prescribed to persons with ID, often with little clinical justification, and without appropriate monitoring for toxicity (Deb and Unwin, 2007; Tsiouris, 2010).
Today, the use of psychotropic treatment of persons with ID should start with an accurate psychiatric diagnosis (Levitas, 2003). Once a diagnosis is made, psychotropic treatment can usually proceed as it would for a person without ID. Unfortunately, little psychopharmacological literature describes the treatment of specific psychiatric illnesses in persons with ID, surrounding the challenge of valid and reliable psychiatric diagnosis. Current psychotropic practice in persons with ID and psychiatric/behavioral disorders is often symptomatic treatment alone, in the absence of a validly identified psychiatric illness (Fletcher et al., 2007).
Psychopharmacological studies can be separated into three broad types, based on whether they focus primarily on the drug or drug class utilized, on psychiatric diagnosis, or the specific etiology of ID. Early studies presented the use of a particular medication (or class) across a range of diagnoses, and/or across a variety of ID etiologies. Later studies have focused on treatment of a single psychiatric disorder or diagnosis (e.g., depression), across a variety of ID etiologies. Increasingly, researchers are convinced of the importance of ID etiology in diagnosis, and the characterization of behavioral phenotypes (see Chapter 18). Future psychopharmacological studies, to improve validity, would focus on a particular medication or class for the treatment of a specific psychiatric disorder, in persons with ID, resulting from a single confirmed etiology (e.g., use of stimulants for attention-deficit/hyperactivity disorder (ADHD) in Fragile X syndrome).
Additionally, very few psychotropic medications have been developed for, or tested in, persons with ID. In new drug development, researchers and regulatory agencies have typically excluded individuals with ID, for a combination of reasons, such as protection of vulnerable research subjects, complex consent issues, metabolic differences, and difficulty of assessing accuracy of treatment response.
There are limited psychotropic studies meeting the contemporary scientific standard of the randomized controlled trial (RCT): double-blind, placebo-controlled methodologies, random assignment of subjects, and standardized measures of efficacy in persons with ID (Courtemanche et al., 2011).
The past
History of the treatment of persons with ID with psychotropic medications
Initial reports focused primarily on the medication utilized, often with little attention paid to psychiatric diagnoses or etiology of ID. As new agents became available, they were given to persons with ID, often in non-specific attempts to ameliorate aggression and self-injurious behavior (SIB); in spite of the suspected fallacy of this practice (Levitas, 2003). Initial agents included the barbiturate anticonvulsants, followed by the first-generation antipsychotics (FGAs), and benzodiazepines; all three have subsequently fallen out of favor (Schroeder et al., 1998). Barbiturates may have significant behavioral side effects (Kalachnik and Hanzel, 2001); similarly, up to 25% of persons with ID treated with benzodiazepines have behavioral disinhibition (Kalachnik et al., 2002). Between the first FGA chlorpromazine (1952) and the first “second-generation” antipsychotic (SGA) clozapine (1989), most FGAs were utilized, although recent use has decreased over concerns regarding efficacy, and propensity for causing serious adverse events (Wilson et al., 1998).
Second-generation antipsychotics have also been widely used, and two (risperidone and aripiprazole) have received approval in the USA for addressing irritability in persons with autism spectrum disorders (ASD) (Ghanizadeh et al., 2014). The hope that other SGAs will be of similar benefit has not yet been supported by systematic research (De Leon et al., 2009). Unwin and Deb (2011) found only six RCTs demonstrating effectiveness of risperidone for problem behaviors in children with ID (with and without ASD); other literature in adults has mostly involved case series (Deb et al., 2007).
Mood stabilizers (particularly anticonvulsants) also have long been used in persons with ID, surrounding frequent co-occurrence of seizure disorders (Harris, 2006). Two recent reviews concluded that both lithium (Deb et al., 2008) and carbamazepine/oxcarbazepine (Jones et al., 2011) appear to have efficacy for aggression/behavioral problems in adults, with methodological limits on interpretation.
Based on efficacy for anxiety, depression, and obsessive-compulsive disorder (OCD) in people with typical IQ, antidepressants have been used in both children and adults with ID, particularly those with comorbid ASD. In ASD, targets have included both core features and repetitive behaviors. In the largest RCT, the selective serotonin reuptake inhibitor (SSRI) citalopram was not better than placebo in addressing repetitive behavior in children with ASD, and produced more adverse events (King et al, 2009); but two smaller studies of SSRIs in adults were more positive for addressing aggression and anxiety (Williams et al., 2010). A recent attempted meta-analysis of tricyclic antidepressants for children with ASD also noted limited and conflicting evidence for efficacy, and significant adverse events (Hurwitz et al., 2012).
Beta-adrenergic blocking medications have been utilized to treat aggression and impulse dyscontrol in persons with ID (Ruedrich and Erhardt, 1999); however, a recent review noted the lack of RCTs supporting this practice (Ward et al., 2013).
Finally, opiate antagonists (naltrexone) have been utilized for high-intensity SIB frequently seen in persons with ID, and several small RCTs have demonstrated efficacy for irritability and hyperactivity in children with ASD (Roy et al., 2015).
The present
Psychotropic treatment of specific psychiatric disorders
Newer studies have focused on the treatment of specific psychiatric disorders, an approach obviously dependent on the validity of the diagnostic process (Fletcher, et al., 2007). Some approaches have utilized objective measures of diagnosis or illness severity, such as cutoff scores on subscales of standardized assessments of psychopathology (e.g., the Behavior Problems Inventory [BPI]; Rojahn et al., 2004), for study inclusion and/or efficacy assessments.
Attention-deficit/hyperactivity disorder
In attention-deficit/hyperactivity disorder (ADHD), stimulants appear effective for motor overactivity, although the response is less robust compared to persons without ID (Aman et al., 2008; Rowles and Findling, 2010). A recent large RCT with methylphenidate was also positive (Simonoff et al., 2013) and atomoxetine use is also supported (Aman et al., 2014). Two small RCTs also supported the alpha-agonists clonidine and guanfacine in children with ADHD and ID (Agarwal et al., 2001; Handen et al., 2008); both drugs caused significant early sedation.
Anxiety disorders
There are no RCTs directly addressing anxiety disorders in persons with ID (King, 2007). Multiple agents have been utilized, including antidepressants, anticonvulsants, benzodiazepines, beta-blockers, buspirone, and antipsychotics; none have an evidence base supporting their use (Davis et al., 2008). The presence of anxiety or OCD did seem to predict benefit from SSRIs used for behavioral disorders (Sohanpal et al., 2007).
Psychotic disorders
Almost no RCTs have attempted to address the treatment of psychotic disorders in persons with ID (De Leon et al., 2009). One early study compared two FGAs for schizophrenia in persons with ID; but methodological problems make interpretation difficult (Menolascino et al., 1985).
Mood disorders
Few studies exist which have focused on drug treatment of mood disorders, particularly in persons with severe ID (Antonacci and Attiah 2008). Although all classes of antidepressants have been utilized for major depression, and mood stabilizers for bipolar disorder in persons with ID, there are no RCTs over the last two decades (Ruedrich et al., 2001).
Self-injurious behavior
There are only a few small RCTs (four with naltrexone, and one with clomipramine) specifically addressing SIB (Gormez et al., 2014), with only weak evidence supporting any of the active drugs over placebo.
Behavior disorders
Oliver-Africano et al. (2009) have described the lack of clinical uniformity of definitions for “challenging behavior” in persons with ID, which may include physical aggression to others, SIB, motor overactivity, property destruction, verbal outbursts, and agitation. Reviews have noted the lack of RCT evidence supporting the use of antidepressants, mood stabilizers, anxiolytics, or opiate antagonists for treating behavioral disorders (Deb and Unwin, 2007) but some support from RCTs for risperidone, particularly in children (Wilner, 2015). However, in a recent multisite RCT comparing haloperidol, risperidone, and placebo for aggression in 80 non-psychotic patients with ID, there were no important differences in efficacy or adverse effects for either antipsychotic medication compared to placebo (Tyrer et al., 2008); nor was active drug cost effective compared to placebo (Tyrer et al., 2009). Still, respondents to a survey of psychiatrists in the UK favored SGAs for aggression and SIB in adults (Unwin and Deb, 2008); although non-medication interventions were favored over any medication.
The future
Drug treatments in ID-related disorders with known etiology
Down syndrome
Surrounding the observation that adults with Down syndrome (DS) develop early-onset Alzheimer-type dementia (Schupf and Sergievsky, 2002); there has been hope that typical treatments for Alzheimer’s dementia would be useful in DS, either in delaying or treating dementia, or possibly enhancing cognitive ability in younger persons with DS. Results to date have been disappointing (Costa and Scott-McKean, 2013). One RCT found that donepezil, a cholinomimetic medication approved for Alzheimer’s, improved cognition in 21 women with DS (Kondoh et al., 2011); but did not in two larger studies of adolescents and young adults with DS without dementia (Kishnani et al., 2009, 2010); and antioxidant therapy was also ineffective (Lott et al., 2011). Memantine, the other medication currently available for Alzheimer’s dementia, did not provide significant cognitive benefit in two other RCTs (Boada et al., 2012; Hanney et al., 2012).
Fragile X syndrome
Attention-deficit/hyperactivity disorder in people with fragile X syndrome (FXS) appears to respond to stimulant medications (Rueda et al., 2009); l-acetylcarnitine (Torrioli et al., 2008) and perhaps divalproex sodium (Torrioli et al., 2010), but not folic acid (Rueda et al. 2009). SSRIs have also been utilized to address anxiety and social aversion in people with FXS (Hagerman et al., 2014). Recent studies have focused on addressing the underlying genetic mechanism of FXS (silencing of the FMR1 gene, resulting in non-expression of the FX protein), which appears to enhance glutaminergic signaling. Both glutaminergic antagonists and gamma-aminobutyric acid (GABA) agonists have been studied; neither approach has been sufficiently effective to date in controlled trials. Minocycline (a tetracyline antibiotic) has been shown to improve mood and anxiety in people with FXS, presumably by promoting neuronal dendritic spine maturation (Hagerman et al., 2014).
Fetal alcohol spectrum disorder
Although no RCTs are available, ADHD in fetal alcohol spectrum disorder (FASD) may respond to stimulants, with hyperactivity/impulsivity more responsive than inattention (Doig et al., 2008); in an uncontrolled trial, neuroleptics provided some benefit in promoting peer relations (Frankel et al., 2006).
Velocardiofacial syndrome
Methylphenidate was effective (and safe) for ADHD in a RCT trial of 34 children/adolescents with velocardiofacial syndrome (VCFS) (Green et al., 2011), and treating mood and anxiety disorders may delay the onset of psychosis (Gothelf et al., 2013).
Williams syndrome
Although no RCTs are available, treatment of ADHD with methylphendiate was successful in 72% of 38 children/adolescents (Green et al., 2012) and 36% of a large sample of persons with Williams syndrome were receiving antidepressants for anxiety, the majority appearing to benefit (Martens et al., 2012).
Prader–Willi syndrome
Stimulants have not been effective in managing weight (Harris, 2006); and topiramate was ineffective in weight management, but helped compulsive skin picking in a small open-label trial (Shapira et al., 2004). SSRIs may have some efficacy in decreasing skin picking (Dykens and Shah, 2003), and a recent RCT with intranasal oxytocin resulted in increased trust and decreased sadness (Tauber et al., 2011).
Autism spectrum disorders
Medications have been utilized in autism spectrum disorders (ASD) to address both the core features of the disorder, accompanying (non-core) symptoms, and/or comorbid psychiatric disorders. Two (risperidone and aripiprazole) have been found in RCTs to be efficacious for treating irritability in children and adolescents with ASD (Ghanizadeh et al., 2014). Psychostimulants help impulsivity and hyperactivity (Posey et al., 2007) and melatonin has been shown to benefit sleep duration and sleep latency, but not awakenings (Rossignol and Frye, 2013). Other RCTs have provided lack of support for secretin (Williams et al., 2012) and for omega-3 fatty acids (James et al., 2011). Tricyclic antidepressants produced contradictory results and many side effects (Hurwitz et al., 2012). Finally, SSRI antidepressants have also been disappointing, showing some possible efficacy for ASD adults with anxiety and OCD (Williams et al., 2010); but are not effective for repetitive behaviors in children, and poorly tolerated (King et al., 2009). Newest areas of research are focused on glutamate antagonists, GABA agonists, and oxytocin (Canitano, 2014).
Side effects
Psychotropic medications have physiological effects in addition to their intended effects, some expected, but with others, unexpected and sometimes dangerous (Wilson et al., 1998). Because psychotropic medications and the neurotransmitter systems they affect are not limited to the central nervous system, they have physiological effects on a number of other organ systems (King, 2007). First-generation antispychotics have a long-recognized risk of producing extra-pyramidal adverse effects, including acute dystonias, motor restlessness, Parkinsonism, and, with long-term use, tardive dyskinesia (Harris, 2006). These risks are somewhat less with the SGAs, but the latter can produce an arguably more debilitating set of metabolic changes – weight gain, insulin resistance with type 2 diabetes, and hyperlipidemia (Frighi et al., 2011; De Kuijper et al., 2013). Most antipsychotics, as well as SSRIs and tricyclic antidepressants (TCAs), also carry a risk of QTc prolongation on the electrocardiogram (Beach et al., 2013). Many psychotropics lower the seizure threshold, particularly dangerous in the 25% of persons with ID with comorbid epilepsy (McGrother et al., 2006). The anticonvulsant mood stabilizers carry risks of electrolyte imbalance, ataxia, sedation, and liver toxicity, and with carbamazepine and lamotrigine, sometimes dangerous rash (Sipes et al., 2011). Many psychotropics have anticholinergic side effects, resulting in dry mouth, constipation, urinary retention, and oculo-visual symptoms (Wilson et al., 1998). All of the above are complicated by commonplace polypharmacy in persons with ID (Edelsohn et al., 2014).
Individuals with ID present a major additional challenge: the difficulty they have in identifying and communicating any adverse effects to their caregivers or clinicians (Wilson et al., 1998). Persons with ID experiencing adverse events from psychotropic medications, particularly those without communicative language, may demonstrate behavioral problems as a result of orthostatic hypotension, motor restlessness, constipation, or a myriad of other distressing adverse events, and are often given additional psychotropic medications, exacerbating the underlying problem (Valdovinos et al., 2005). A number of methodologies involving objective rating scales have been developed to assess for and quantify psychotropic side effects, particularly for the antipsychotic medications, including the Matson Evaluation of Drug Side Effects (MEDS; Matson and Mahan, 2010). Others have offered publications written and illustrated at the developmental level of individuals with ID, in order to educate about the risks/benefits of psychotropic medications (Aman et al., 2007).
Conclusions
Decision-making involving psychotropic medications for persons with ID is difficult, with little evidence base guiding therapeutics in particular for psychiatric disorders, and even less for non-syndrome-related behavioral disorders. Several groups have provided clinical consensus to guide treatment teams, notably the Psychotropic Medications and Developmental Disabilities: The International Consensus Handbook (Reiss and Aman, 1998), and the Expert Consensus Guideline Series (Rush and Frances, 2000). Deb and colleagues have provided comprehensive reviews of several classes of psychotropics, regarding the strength of evidence supporting use in treating behavioral disorders (Deb, et al., 2007, 2008; Sohanpal et al., 2007). Finally, the World Psychiatric Association (WPA) Section of the Psychiatry of ID has recently published a series of guidelines outlining best practices with psychotropic medications (Deb et al., 2010). Although specifically aimed at the treatment of behavioral disorders, they offer an excellent framework for all psychotropic practice in ID, highlighting:
1. Completing a comprehensive assessment.
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