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50 years of hurdles and hope in anxiolytic drug discovery.

ABSTRACT: Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these efforts has been disappointing, as promising results with novel agents in rodent studies have very rarely translated into effectiveness in humans. Here, we analyse the major trends from preclinical studies over the past 50 years conducted in the search for new drugs beyond those that target the prototypical anxiety-associated GABA (?-aminobutyric acid)-benzodiazepine system, which have focused most intensively on the serotonin, neuropeptide, glutamate and endocannabinoid systems. We highlight various key issues that may have hampered progress in the field, and offer recommendations for how anxiolytic drug discovery can be more effective in the future.

SUBMITTER: Griebel G

PROVIDER: S-EPMC4176700 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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50 years of hurdles and hope in anxiolytic drug discovery.

Griebel Guy G Holmes Andrew A

Nature reviews. Drug discovery 20130901 9

Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these ...[more]

PMID: 23989795

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Project description:ImportanceUS adults born from 1965 to 1996 had high exposure to controlled medications, yet little is known about how this exposure has affected them over time. Prescription drug misuse (PDM) has increased among adults in the past 2 decades, with related increases in emergency department visits, overdoses, and deaths.ObjectivesTo identify 32-year PDM trajectories involving opioids, stimulants, and sedatives or tranquilizers and to examine associations between these PDM trajectories and substance use disorder (SUD) symptoms in adulthood as well as between baseline characteristics and PDM trajectories.Design, setting, and participantsThis cohort study included 11 cohorts of adolescents who were followed up longitudinally from age 18 years (study start, 1976-1986) to age 50 years (2008-2018) in the Monitoring the Future (MTF) study, which included a national multistage random sample of US 12th grade students. Baseline surveys (modal age 18) were self-administered in classrooms. Ten follow-ups were conducted by mail. Data analysis was conducted from December 2020 to October 2021.Main outcomes and measuresSociodemographic variables were measured at baseline. PDM and SUD symptoms were measured at baseline and every follow-up. Latent profile analysis (LPA) was used to create PDM trajectory profiles. Associations between these PDM trajectories, SUD symptoms, and baseline sociodemographic characteristics were examined.ResultsThe sample of 26 575 individuals was 50.8% (95% CI, 50.2%-51.4%) female and 79.3% (95% CI, 78.8%-79.8%) White. The baseline response rate ranged from 77% to 84%, and the 32-year retention rate was 53%. In adjusting for attrition, 45.7% (95% CI, 44.9%-46.4%) of the respondents reported past-year PDM at least once during the 32-year reporting period. Among those who reported PDM, the prevalence of poly-PDM was 40.3% (95% CI, 39.3%-41.3%). Based on LPA, the number of class-specific PDM trajectories ranged from 4 (prescription opioids) to 6 (prescription stimulants). For the class-combined analyses, we identified 8 PDM trajectories consisting of early peak trajectories (eg, age 18 years), later peak trajectories (eg, age 40 years), and a high-risk trajectory (eg, high frequency PDM at multiple ages). All PDM trajectories were associated with increased odds of developing SUD symptoms in middle adulthood, especially the later peak and high-risk trajectories compared with early peak trajectories (eg, peak at age 40 years: adjusted odds ratio [aOR], 5.17; 95% CI, 3.97-6.73; high-risk: aOR, 12.41; 95% CI, 8.47-18.24). Baseline characteristics associated with a high-risk trajectory were binge drinking (aOR, 1.69; 95% CI, 1.13-2.54), cigarette smoking (aOR, 2.30; 95% CI, 1.60-3.29), and marijuana use (aOR, 3.78; 95% CI, 2.38-6.01). More recent cohorts (eg, 1985-1986) had a higher risk of belonging to later peak PDM trajectories (ages 40 and 45 years) than the 1976-1978 cohort (age 40 years peak: aOR, 2.49; 95% CI, 1.69-3.68).Conclusions and relevanceIn this cohort study, adults with later peak PDM trajectories were at increased risk of SUD symptoms in middle adulthood. These findings suggest the need to screen for PDM and SUD from adolescence through middle adulthood.

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50 years of hurdles and hope in anxiolytic drug discovery.

Publications

50 years of hurdles and hope in anxiolytic drug discovery.

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