by James O’Hanlon, Ph.D., Psychopharmacologist

In 2005, neurologists at Johns Hopkins University published a postmortem study comparing 11 individuals with ASD and as controls, 11 typically developing individuals.1   Groups were matched with respect to age at death, 5 to 44 years. All of the autistic brains but none of the control brains showed unequivocal signs of chronic neuroinflammation that varied regionally in severity, the cerebellum being the worst. Authorities on the pathophysiology of autism immediately recognized the importance of this study. It clarified hitherto inexplicable findings; e.g., selective degeneration of neurons in the autistic cerebellum. It also suggested that anti-inflammatory drugs might be relatively safe and effective treatment for core and associated symptoms of ASD. Neuroinflammation in the autistic brain has been repeatedly confirmed and today no authority doubts it is part of the pathophysiology of autism. The neuroinflammatory process is well understood. What remains uncertain is how neuroinflammation starts and how it usually stabilizes at a level that interferes with brain functions without being life-threatening.

Microglia are key players in this process. They are the free-standing, resident immune cells in the central nervous system. In the healthy brain, microglia are quiescent but vigilant. They recognize bacterial or viral components and those from damaged or dead neurons using molecular- pattern recognition receptors. When so stimulated, microglia quickly progress into the first (M1) of two activated states. They rapidly multiply and morph into amoeba-like cells that follow a chemical gradient to the source of stimulation. As they approach the target, microglia release proteins – pro-inflammatory cytokines – that promote local inflammation.  In closer proximity they release various cytotoxic substances that disrupt cell membranes. Microglia then engulf and digest the remains. To limit the destructive immune response, microglia shift into the second (M2) activated state, whereupon they release anti-inflammatory cytokines and other agents that promote healing.

The balance between pro-and anti-inflammatory processes is intricate. In ASD it seems, the balance is partially shifted to the pro-inflammatory side. This is not only evident in postmortem studies; it has been shown in living individuals. Twenty, healthy and generally high-functioning men with ASD were compared with 20 age- and IQ-matched normally developing men by positron emission tomography (PET) using a radiotracer selective for activated microglia.2   Imagery of radiotracer binding to microglia was significantly greater for the men with ASD than the controls in every brain region studied, with the largest difference in the cerebellum.

Pioglitazone is a contender to be the first anti-inflammatory drug to be approved for treating ASD. The drug was originally developed and later approved by FDA as an antidiabetic drug because of its sensitizing effect on insulin receptors of adipose cells. But this is now known to be an indirect consequence of the more basic effect the drug has upon gene production of regulatory proteins in many quite different cell types, including microglia. Pioglitazone binds to and activates the peroxisome proliferator-activated receptor-gamma (PPAR  ). After pioglitazone binds to PPAR, the entire complex migrates to the cell nucleus where it causes certain genes to increase transcription of particular proteins and inhibits other genes from transcribing proteins. The entire process is too complex to describe here but the net effect on an inflammatory reaction is easily stated. Activated microglia are transformed from M1 to M2 states as their effects shift from pro- to anti-inflammatory.

The first team to study the effects of pioglitazone in pediatric patients with ASD was led by an immunologist who, it seems, conducted the study in his own private practice.3  A series of 25 children and adolescents, aged 3 to 17, were openly treated with pioglitazone for 4 months. Treatment was effective for reducing aberrant behaviors in 76% of the participants. Improvement was inversely related to the participants’ age; i.e., the younger the child the more he/she improved. Other than slightly and transiently elevated liver enzymes and white blood cell counts in a few children, no side effects were observed. The second trial compared adjunctive pioglitazone versus placebo treatments, double-blind, combined with standard risperidone therapy.4  Separate groups of 20 children with ASD (aged 4-12) received each treatment for 10 weeks. Relative to placebo, pioglitazone significantly enhanced the beneficial effects of risperidone on hyperactivity, irritability and social withdrawal.  Side effects did not differ significantly between groups and none was serious. The third pioglitazone study generally followed a standard format for establishing safety, obtaining preliminary evidence of efficacy and establishing the maximum tolerated dose within the range tested.5 The investigators measured changes in pro-inflammatory and anti-inflammatory cytokines in plasma, which if occurring in the brain, might explain behavioral effects of pioglitazone. Twenty-seven children with autism (aged 5-12) completed the 4-month open trial. A broad battery of behavioral tests was employed to measure significant improvements in the following: 1) global behavioral disturbance, 2) social withdrawal, 3) irritability, 4) anxiety, 5) hyperactivity, 6) repetitive behavior and 7) obsessive-compulsive behavior. The plasma concentration of a pro-inflammatory cytokine dropped while that of an anti-inflammatory cytokine rose significantly during the trial. No serious side effects occurred, though again, a few children showed a slight drop in white blood cell count that resolved spontaneously during or after the trial.

Anti-inflammatory drugs are targeted on the pathophysiology of ASD not on behavioral symptoms that occur as consequence.  Many of those symptoms are assumed to be caused or at least exacerbated by neuroinflammation. Thus, when a drug successfully reduces neuroinflammation, one would expect a global reduction in ASD symptoms. Pioglitazone appears to have done this in early trials.

1 Vargas DL, Nascimbene C, Krishnan C, et al. Ann Neurol 2005;57: 67-81

2 Suzuki K, Sugihara G, Ouchi Y, et al. JAMA Psychiatry 2013; 70: 49-58

3 Boris M, Kaiser CC, Goldblatt A, et al. J Neuroinflammation 2007; 4:3

4 Ghaleiha A, Rasa SM, Nikoo M, et al. Psychiatry Res 2015; 229: 181-187

5 Capano L, Dupuis A, Brian J, et al. Mol Autism 2018; 9:59