Varenicline in Autistic Disorder: Hypothesis and Case Report of Single-Patient Crossover

To the Editor:

A utism spectrum disorders (ASDs) are a set of complex neurodevelopmental disorders with difficulties in reciprocal social interaction, abnormalities in communication and language, and patterns of repetitive or stereotypic behavior and a restricted range of interest (Fombonne 1999). ASDs affect nearly 1 in 110 children, and affect four times as many boys as girls. Comorbid symptoms are common and include hyperactivity, irritability, seizures, sleep problems, gastrointestinal disorders, sensory abnormalities, and metabolic dysregulation (Coury 2010). There is no pharmacotherapy proven effective for treating the core deficits of ASD. It has become evident that both genetic and environmental factors contribute to autism susceptibility (Courchesne et al. 2007; Ramocki and Zoghbi 2008; Südhof 2008; Geschwind 2009), and some of these genetic factors have been identified (Cook and Scherer 2008; Levitt and Campbell 2009).

An important strategy for identifying suitable biochemical molecules and pathways to target for the treatment of core deficits in ASD rests strongly on identifying endophenotypes and biomarkers. We present a rationale as well as results from a single case report that targeting neuronal nicotinic acetylcholine receptors (nAChR) with drugs specific to the α4β2 nAChR subtype is likely to be useful for ASD treatment. This rationale is based on integrating evidence from multiple types of studies, including our own (Cheng et al. 2009), using postmortem, genetic, functional, and molecular neurobiological methodologies showing that the early loss of nAChRs and their functions, caused by mechanisms yet to be identified, may contribute to the etiology of ASDs.

The extensive deficit of α4β2 nAChR has been observed in postmortem brains from some individuals with ASD (Adler et al. 1993; Dalack et al. 1999; Perry et al. 2001). High-affinity [3H]epibatidine binding to α4β2 nAChRs is significantly reduced in the frontal, parietal, and cerebellar cortex of individuals with ASD compared with age-matched controls. In addition, immunohistochemical analyses indicate that the loss of [3H] epibatidine correlates with reduced expression of the α4 and β2 nAChR protein subunits, but not their mRNA, particularly in the cerebellar cortex, suggesting that the reduction in nAChR subunit levels resulted from an impaired posttranslational mechanism. These postmortem studies, limited as they may be in numbers, provide a reasonable scientific justification for exploratory trials of drugs that can upregulate and/or activate α4β2 nAChRs, and thus compensate for their loss both physically and functionally in some individuals with ASD (Adler et al., 1993; Dalack et al., 1999; Perry et al. 2001).

Neuronal nAChRs are ion channels permeable to both Na+ and Ca++ cations and formed by assembly of subunits termed α2 to α10 and β2 to β4. These channels are typically heteropentamers, with the exception of the α7 nAChR, which can be a homopentamer (Sargent 1993; Lindstrom, 1996, 1997). In the central nervous system, nAChRs regulate the release of many different neurotransmitters including acetylcholine, dopamine, γ-aminobutyric acid (GABA), glutamate, and serotonin at presynaptic sites (McGehee and Role, 1996) and mediate fast synaptic transmission at postsynaptic sites (Zhang et al., 1996; Frazier et al., 1998a, b). These pleotropic functions of nAChRs modulate an unusually broad range of physiological processes including reward, analgesia, anxiety, affect, locomotion, attention, mood, learning, memory, and executive function (Miwa et al. 2011). In addition to their role in nicotine addiction, nAChR dysfunctions are also implicated in other disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia, attention-deficit/hyperactivity disorder (ADHD), anxiety disorders, Tourette's syndrome, and depression (Newhouse and Kelton 2000; Newhouse et al. 2004; Mineur and Picciotto 2010). It is to be noted that nAChRsplay a role in repetitive behavior symptoms in Tourette's syndrome, obsessive compulsive disorder, and ADHD, and that nicotine or its analogs have demonstrated potential to treat repetitive and excessive behaviors in these disorders (Sanberg et al. 1997; Levin and Simon 1998; Wilens et al. 1999; Carlsson 2001; Pasquini et al. 2005).

Varenicline (CHANTIX^®) is a drug approved by the Food and Drug Administration (FDA) for smoking cessation therapy. It is a nonaddictive partial agonist of the α4β2 nAChRs (Coe et al. 2005) and therefore of interest for treatment of ASD. Although varenicline is a full agonist of the α7 AChR (Mihalak et al. 2006), specificity for α4β2 nAChRs is achievable when it is used clinically at the recommended lower doses for antismoking therapy (Niaura et al. 2006). Therefore, it has become one of the most widely used smoking cessation drugs, with millions treated worldwide. It shows little in the way of sympathetic and parasympathetic complications from cross activation of ganglionic α3α5β4 nAChRs. Interestingly, much like nicotine, varenicline can upregulate α4β2 nAChRs in vitro. Finally, as a partial agonist, it has the added benefit of providing chronic non-desensitizing, low-level channel activation of α4β2 nAChRs (Papke et al. 2011) and possibly associated downstream intracellular signaling pathways. Varenicline can change behaviors in some smokers, and the FDA public health advisory warns of increased suicidal thoughts and actions. It is important to note, however, that the increase in suicidal thoughts and actions resulting from using varenicline may occur only in individuals with comorbid neuropsychiatric conditions, including schizophrenia, a disorder in which excessive smoking has been noted for decades (Adler et al. 1993; Dalack et al.1999). There is some evidence to support the idea that varenicline use in itself is not associated with an increased risk for depression or suicidal thoughts (Gunnell et al. 2009). Another significant difference to note is that, unlike in schizophrenia, the prevalence of smoking in individuals with ASD is very low (Bejerot and Nylander 2003), possibly because the loss of α4β2 nAChRs occurs early in development. The following case study suggests that varenicline or drugs with related properties that target α4β2 nAChRs may be useful in treating core deficits in ASD.

Case Report

A 9-year-old boy had an established diagnosis of autistic disorder, made at 3 years of age because of delayed language (he did not speak until he was almost 4 years of age), idiosyncratic language, stereotyped movements and play, sensory intolerances, unresponsiveness to instruction, poor social skills, poor eye contact, emotional distance, disregard of people, heedlessness of real danger (darting, running into street), and irrational fear of harmless situations/objects. After some instruction in behavior modification, his parents trained him to use words and observe some social amenities. Once he attained language, it became obvious that he was high-functioning, with clinical intelligence quotient (IQ) estimate above average. Because of associated hyperactivity, he began low-dose atomoxetine at 7 years of age, up to 30 mg a day, but then lowered to 10 mg a day. The main reason for lowering the dose was a “depressed/suppressed personality” on the higher dose. His parents found that 10 mg atomoxetine allowed him to continue succeeding academically (in a regular classroom) without the personality change.

His parents had heard of the nicotinic receptor deficiency hypothesis for autism described previously, and requested a trial of varenicline, knowing the risks. A cautious trial was initiated, with availability of phone consultation; the parents were given a copy of the Ohio Autism Clinical Impressions Scale to plot his progress. At that point (age 9) he weighed ∼40 kg. He started with half of a 0.5 mg tablet per day for a week and then was given 0.5 mg/day. Within a month, observers outside the family were spontaneously commenting about the improvement in conversational ability, social interaction, and reasoning/coherence. He was continuing his 10 mg atomoxetine. However, the combination of the two drugs seemed to bring back the depressed/suppressed personality that he had with the higher dose of atomoxetine, and his parents decided to stop varenicline. Within a week he had regressed to his status prior to starting varenicline, including frequent self-talking, less socializing, and patterned pacing with some finger stereotypy. The parents restarted varenicline 0.5 mg/day, and within a week he regained the improvement he had shown after a month of varenicline. The parents stopped the atomoxetine, and the depressed/suppressed personality resolved. The patient's scores on the Ohio Autism Clinical Impressions Scale are shown in Table 1 for before varenicline, after a month of varenicline, after varenicline had stopped for a week, and after varenicline resumed. There were no gastrointestinal side effects or sleep disturbance, but he developed dry eyes, which were treated with eye drops. In a written summary, his mother reported the following:

Discussion

To our knowledge, this is the first report of an individual with autism treated with varenicline, an α4β2 nicotinic receptor partial agonist. The unintended ABAB treatment experience made an experiment of nature with rather encouraging results. The parents were so impressed with the results that for several months they continued to buy varenicline for him at considerable expense (because the off-label use is not covered by their insurance). They share the prescriber's concerns about long-term safety and volunteered to have this case study published to promote research in a more controlled fashion.

With any open trial, there is always the possibility of placebo effect. This has been especially noted in autism, where parents are desperate to find improvement. It is also especially likely when the patient or family request a specific treatment, as in this case. The possibility of placebo response seems less likely in view of other observers (e.g., teacher, parents of peers), who did not know about the treatment, spontaneously commenting on the improvement. The obvious side effects (interaction with atomoxetine and dry eyes) should also have detracted from placebo response; however, the parents remained impressed enough to restart the drug after stopping it because of dissatisfaction with the side effects. Ultimately, this question can only be resolved by a placebo-controlled randomized trial.

The apparent interaction with atomoxetine deserves some comment. Atomoxetine is a selective norepinephrine reuptake inhibitor. Varenicline is a partial nicotinic receptor agonist. Therefore, both increase neurotransmission, but on opposite sides of the cholinergic–adrenergic balance. It is not clear why the two drugs together produced an additive side effect similar to that of a higher dose of atomoxetine. The varenicline package insert mentions that there is no interaction with bupropion, another adrenergic drug. Of course, atomoxetine blood levels and therefore effective atomoxetinedose, can be increased by any drug that inhibits CYP2D6, but this has not been a problem in typically developing patients. A speculative explanation could be that the additive/synergistic effects observed may be related to the ability of atomoxetine to indirectly modulate the same nicotinic cholinergic pathways targeted by varenicline (Davis and Gould 2007).

Regardless of the effect on ADHD symptoms, for which other treatments are available, the possibility of effects on core autism symptoms of social and communication impairment demands further exploration. This should be done in controlled conditions with careful safety monitoring. The package insert lists a higher rate of insomnia (∼15%), abnormal dreams (∼7%), and nightmares (2%) than with placebo (<2%, 0.6%, and 0%, respectively), which could be problematic in a disorder already notorious for sleep delay and midsleep awakening. The reported dysgeusia (∼6% compared with 0.5% with placebo) could be a problem with the already idiosyncratic food preference of many children with autism, as could the nausea (12% vs. 1%) and abdominal pain (>3% vs. <1%). The patient reported here had none of those side effects but did have the dry eye symptoms that are listed as rare. We might hope that they will also be rare in a larger sample of individuals with autism, but it is possible that dry eyes will be more frequent in the presence of autism. The recent reports of suicidal symptomatology with varenicline suggest that large scale clinical trials of varenicline for individuals with ASD require careful monitoring of suicidal ideation, given the heterogeneity of causes postulated for ASD, with possible overlap with schizoaffective disorders (Kirov et al. 2009).

The dosage may well be the most important issue to be resolved prior to a randomized clinical trial, to test safety and efficacy in autism. The boy reported here had a notable response to 0.25 mg per day despite a body weight >40 kg. We do not know whether this is characteristic of autism or just an idiosyncratic sensitivity of this patient to medication. Therefore, a dose-finding study, starting with adults, or possibly adolescents, with ASD, would be the next logical step in preparing for a randomized clinical trial.

Conclusion

These encouraging results from an ABAB experiment of nature warrant further controlled research, but do not justify clinical recommendations at this time. A logical research sequence might be first a dose-finding study in adults with autism, then a placebo-controlled pilot trial in adults and adolescents, then a multisite randomized clinical trial first in adults and adolescents, and finally in children with autism. We should emphasize the very preliminary nature of this report. An anecdotal case report, even with a fortuitous naturalistic ABAB experiment of nature, does not constitute a basis for clinical recommendations, but rather an indication for research on the possibilities.

Disclosures

Dr. Arnold has received research funding or advisory board honoraria from AstraZeneca, BioMarin, CureMark, Lilly, Noven, Novartis, Seaside Therapeutics, Shire, and Targacept. Dr. Aman has received consulting honoraria or research support from Biomarin, Bristol-Myers Squibb, Johnson & Johnson, Forrest, Roche, and Supernus. Dr. Anand has no affiliations to report.