Pharmacogenetic Study of Serotonin Transporter and 5HT2A Genotypes in Autism

Najjar, Fedra; Owley, Thomas; Mosconi, Matthew W.; Jacob, Suma; Hur, Kwan; Guter, Stephen J.; Sweeney, John A.; Gibbons, Robert D.; Cook, Edwin H.; Bishop, Jeffrey R.

doi:10.1089/cap.2014.0158

Cited by 14 publications

(27 citation statements)

References 19 publications

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“…The primary predictors of interest here were the two-way interactions. All analyses controlled for age and sex which were predefined covariates in our data analysis plan and consistent with other clinical analyses of this study sample [17] [16]. We evaluated the influence of demographic variables including race (dichotomized as Caucasian or non-Caucasian), pubertal status [pre-pubertal defined as a Tanner Stage (TS) <3 or age <144 months if TS was not assessed; post-pubertal was defined as a TS ≥3 or age ≥144 months if TS was not assessed], weight, final dose (for ABC-CV-Irr models), and non-verbal IQ (for ABC-CV-Irr models), but these factors were not included in the final models as they did not influence the pattern or significance of the pharmacogenetic findings.…”

Section: Methodsmentioning

confidence: 97%

“…Study samples from two escitalopram pharmacogenetic studies (5-HTTLPR of the serotonin transporter target) using similar enrollment, assessment, and treatment strategies were combined for this pharmacogenetic analysis [17] [16]. …”

Section: Methodsmentioning

confidence: 99%

“…Participants were initiated on a dose of 2.5 mg escitalopram at the beginning of week 1 of the study followed by weekly increases to 5, 10, 15, and finally 20 mg po qd. If participants experienced adverse effects, the titration escalation was altered to maintain a tolerated dose [16, 18]. The first of the two treatment studies used in this pharmacogenetic analysis was a 10 week study of escitalopram in the treatment of ASD [17, 18].…”

Section: Methodsmentioning

confidence: 99%

“…In that study it was recognized that no further improvements in the ABC-CV-Irr were observed from 6–10 weeks [18]. Thus the follow-up study was designed as a 6-week investigation [16] with assessments and dosing strategies completed for the purposes of further assessing the clinical benefit of escitalopram as well as pharmacogenetic analyses of participants from both studies using the first 6 weeks of treatment from Owley et al merged with the 6-week study of Najjar et al…”

Section: Methodsmentioning

confidence: 99%

“…The serotonin transporter and serotonin-2A genes ( SLC6A4 and HTR2A , respectively) have been investigated in pharmacogenetic studies of ASD with mixed results [16, 17]. To our knowledge, genetic variation in drug metabolism has not been extensively studied in relation to SSRI treatment outcomes in ASD.…”

Section: Introductionmentioning

confidence: 99%

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Escitalopram pharmacogenetics

Bishop

Najjar

Rubin

et al. 2015

Pharmacogenetics and Genomics

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Purpose Selective serotonin reuptake inhibitors such as escitalopram are commonly used to treat patients with Autism Spectrum Disorder (ASD), but there are individual differences in treatment response and tolerability. CYP2C19 encodes the primary enzyme responsible for escitalopram metabolism and we investigated whether polymorphisms in CYP2C19 were related to symptoms and dosing in a pharmacogenetic study of ASD. Methods Participants completed the Aberrant Behavior Checklist-Community Version (ABC-CV) weekly for 6 weeks. Escitalopram was initiated at a dose of 2.5 mg qd with weekly increases to 20 mg unless intolerable side-effects occurred. Three CYP2C19 metabolizer groups, including ultrarapid, extensive, and reduced metabolizers, were examined in relation to symptom improvement and tolerated dose. Results ABC-CV scores improved over the course of treatment (p<0.0001). There were no differences identified in the rate of improvement across metabolizer groups for the ABC-CV-irritability subscale, which was the primary outcome for clinical symptoms. There was a trend for a metabolizer group by time interaction with respect to dose (p=0.10). This interaction was driven by the linear rate of change from week 1 to study endpoint between the reduced metabolizers and ultrarapid metabolizer groups (p=0.05). Post hoc analyses identified significant differences in the rate of dose escalation between ultrarapid metabolizers and extensive metabolizers and for ultrarapid metabolizers compared to reduced metabolizers (p’s<0.04), whereby ultrarapid metabolizers exhibited a slower rate of change in dose over time. Conclusion CYP2C19 ultrarapid metabolizers were associated with reduced tolerance to a fixed titration schedule of open label escitalopram in this ASD study sample. Possible explanations may involve the altered kinetics of faster metabolizers or previously unknown activities of escitalopram metabolites.

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Section: Methodsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Escitalopram pharmacogenetics

Bishop

Najjar

Rubin

et al. 2015

Pharmacogenetics and Genomics

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Effect of Fluoxetine on Obsessive-Compulsive Behaviors in Children and Adolescents With Autism Spectrum Disorders

Reddihough

Marraffa

Mouti

et al. 2019

JAMA

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IMPORTANCE Selective serotonin receptor inhibitors are prescribed to reduce the severity of core behaviors of autism spectrum disorders, but their efficacy remains uncertain.OBJECTIVE To determine the efficacy of fluoxetine for reducing the frequency and severity of obsessive-compulsive behaviors in autism spectrum disorders. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, placebo-controlled clinical trial. Participants aged 7.5-18 years with autism spectrum disorders and a total score of 6 or higher on the Children's Yale-Brown Obsessive Compulsive Scale, modified for pervasive developmental disorder (CYBOCS-PDD) were recruited from 3 tertiary health centers across Australia. Enrollment began November 2010 and ended April 2017. Follow-up ended August 2017. INTERVENTIONS Participants were randomized to receive fluoxetine (n = 75) or placebo (n = 71). Study medication was commenced at 4 or 8 mg/d for the first week, depending on weight, and then titrated to a maximum dose of 20 or 30 mg/d over 4 weeks. Treatment duration was 16 weeks. MAIN OUTCOMES AND MEASURESThe primary outcome was the total score on the CYBOCS-PDD (scores range from 0-20; higher scores indicate higher levels of maladaptive behaviors; minimal clinically important difference, 2 points) at 16 weeks postrandomization, analyzed with a linear regression model adjusted for stratification factors (site, age at baseline, and intellectual disability), with an additional prespecified model that included additional adjustment for baseline score, sex, communication level, and imbalanced baseline and demographic variables. RESULTS Among the 146 participants who were randomized (85% males; mean age, 11.2 years), 109 completed the trial; 31 in the fluoxetine group and 21 in the placebo group dropped out or did not complete treatment. The mean CYBOCS-PDD score from baseline to 16 weeks decreased in the fluoxetine group from 12.80 to 9.02 points (3.72-point decrease; 95% CI, −4.85 to −2.60) and in the placebo group from 13.13 to 10.89 points (2.53-point decrease; 95% CI, −3.86 to −1.19). The between-group mean difference at 16 weeks was −2.01 (95% CI, −3.77 to −0.25; P = .03) (adjusted for stratification factors), and in the prespecified model with further adjustment, it was −1.17 (95% CI, −3.01 to 0.67; P = .21). CONCLUSIONS AND RELEVANCEIn this preliminary study of children and adolescents with autism spectrum disorders, treatment with fluoxetine compared with placebo resulted in significantly lower scores for obsessive-compulsive behaviors at 16 weeks. Interpretation is limited by the high dropout rate, null findings of prespecified analyses that accounted for potentially confounding factors and baseline imbalances, and CIs for the treatment effect that included the minimal clinically important difference.

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