Preliminary investigation of lithium for mood disorder symptoms in children and adolescents with autism spectrum disorder.

OBJECTIVE: Children with autism spectrum disorder (ASD) have higher rates of comorbid psychiatric disorders, including mood disorders, than the general child population. Although children with ASD may experience irritability (aggression, self-injury, and tantrums), a portion also experience symptoms that are typical of a mood disorder, such as euphoria/elevated mood, mania, hypersexuality, paranoia, or decreased need for sleep. Despite lithium's established efficacy in controlling mood disorder symptoms in the neurotypical population, lithium has been rarely studied in children with ASD. METHODS: We performed a retrospective chart review of 30 children and adolescents diagnosed with ASD by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria who were prescribed lithium in order to assess target symptoms, safety, and tolerability. Clinical Global Impressions - Improvement (CGI-I) ratings were performed by two board-certified child psychiatrists with expertise in ASD. CGI-I scores were dichotomized into "improved" (CGI-I score of 1 or 2) or "not improved" (CGI-I score ≥3). RESULTS: Forty-three percent of patients who received lithium were rated as "improved" on the CGI-I. Seventy-one percent of patients who had two or more pretreatment mood disorder symptoms were rated as "improved." The presence of mania (p=0.033) or euphoria/elevated mood (p=0.041) were the pretreatment symptoms significantly associated with an "improved" rating. The mean lithium blood level was 0.70 mEq/L (SD=0.26), and the average length of lithium treatment was 29.7 days (SD=23.9). Forty-seven percent of patients were reported to have at least one side effect, most commonly vomiting (13%), tremor (10%), fatigue (10%), irritability (7%), and enuresis (7%). CONCLUSIONS: This preliminary assessment of lithium in children and adolescents with ASD suggests that lithium may be a medication of interest for those who exhibit two or more mood disorder symptoms, particularly mania or euphoria/elevated mood. A relatively high side effect rate merits caution, and these results are limited by the retrospective, uncontrolled study design. Future study of lithium in a prospective trial with treatment-sensitive outcome measures may be indicated.

Methylphenidate restores novel object recognition in DARPP-32 knockout mice.

Previously, we have shown that Dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32) knockout mice required significantly more trials to reach criterion than wild-type mice in an operant reversal-learning task. The present study was conducted to examine adult male and female DARPP-32 knockout mice and wild-type controls in a novel object recognition test. Wild-type and knockout mice exhibited comparable behavior during the initial exploration trials. As expected, wild-type mice exhibited preferential exploration of the novel object during the substitution test, demonstrating recognition memory. In contrast, knockout mice did not show preferential exploration of the novel object, instead exhibiting an increase in exploration of all objects during the test trial. Given that the removal of DARPP-32 is an intracellular manipulation, it seemed possible to pharmacologically restore some cellular activity and behavior by stimulating dopamine receptors. Therefore, a second experiment was conducted examining the effect of methylphenidate. The results show that methylphenidate increased horizontal activity in both wild-type and knockout mice, though this increase was blunted in knockout mice. Pretreatment with methylphenidate significantly impaired novel object recognition in wild-type mice. In contrast, pretreatment with methylphenidate restored the behavior of DARPP-32 knockout mice to that observed in wild-type mice given saline. These results provide additional evidence for a functional role of DARPP-32 in the mediation of processes underlying learning and memory. These results also indicate that the behavioral deficits in DARPP-32 knockout mice may be restored by the administration of methylphenidate.

The effect of cocaine on rotarod performance in male C57BL/6J mice.

There is surprisingly little research examining the effect of cocaine on motor learning. Given that changes in motor activity can confound behavioral assays of learning and memory a direct assessment of cocaine on motor learning seems warranted. The present study was conducted to examine the effect of cocaine on motor learning using an accelerating rotarod test in adult male C57BL/6J mice. Mice were given an injection of either saline or cocaine (10mg/kg, i.p.) for 6 consecutive days prior to rotarod training (Pre-exposure). In the first phase of training (Phase I), mice were given an injection of either saline or cocaine 10min prior to the start of each day's training on the rotarod for 6 consecutive days. In the second phase (Phase II), half the animals continued to receive the same drug during training, while the other half were switched from saline to cocaine or from cocaine to saline. All mice exhibited motor learning as evidenced by an increased latency to fall across days. Animals that received cocaine injections exhibited significantly longer latencies to fall on days 3-6 compared to those mice receiving saline. This enhanced performance was lost when cocaine-injected animals were switched to saline on day 7. It is hypothesized that the performance enhancing effects of cocaine are due to the increased stamina and/or psychomotor stimulation and not the result of enhanced motor learning as the increment in performance was lost when the drug was discontinued.