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Open Access Publications from the University of California

Scholarly Works (7 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2019)

The dawn of a new era of medicine has begun as clinicians and researchers shift their focus to more individual-centric diagnostic, treatment, and disease management strategies. Precision medicine is a multidisciplinary approach to human health care that takes into account a person’s genetic makeup, behaviors, and environmental factors when evaluating pathophysiology, tailoring treatments, and designing novel therapeutic moieties. In this dissertation I break down the critical subfields of this discipline to explain and apply the emerging tools and techniques we now have at our disposal to better understand the underlying biology of complex human psychiatric disorders.

We begin with pharmacokinetics and pharmacodynamics, two branches of precision medicine that are involved directly with the temporal dynamics of pharmaceutical therapies and aid in disentanglement of how the body processes drugs versus how the drugs affect our bodies. I discuss detailed research across three separate drugs; risperidone, methamphetamine, and nicotine, integrating quantitative metabolic studies, genetic assessment, neuroimaging, and receptor analysis to clearly define inter-patient variability in risk and response.

Following this is work I accomplished in the realm of gene and environment interactions in young children experiencing anxiety disorders, which over time, led to what I hold as my largest contribution to the personalized medicine field; microbiome and host interactions. I am attempting to unlock a more direct, biological mechanism to something known as antipsychotic-induced weight gain (AIWG) through the examination of bile acids and the gut microbiome and their crosstalk and interplay with host physiology. Results are abundant throughout this document and each study presented here within brings a unique piece of the precision medicine puzzle to the table.

Pharmacokinetics, pharmacodynamics, genomic technology, gene-environment interactions, and the host-microbiome axis are the salient concepts in my toolbox of personalized medicine techniques that I believe can be leveraged in a variety of combinations to accomplish large goals in the medical and biotechnology fields. Whether it be through careful patient assessment with companion diagnostics, proper medication selection based on risk vs. reward value in harmony with an individual’s personal makeup, perseverance of high level disease progression and treatment monitoring, or even one day tailoring drug discovery to the highly specific receptors and biological pathways involved in these grievous diseases, it is clear precision medicine will pave the way for a better life for many people in the future.

    Cover page: Leveraging the Tools and Techniques of Precision Medicine to Better Understand the Biological Underpinnings of Psychiatric Disorders and Psychotropic Treatment Effects
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2021)
    Chronic methamphetamine use is linked to abnormalities in brain structure, which may reflect neurotoxicity related to metabolism of the drug. As the cytochrome P450 2D6 (CYP2D6) enzyme is central to the metabolism of methamphetamine, genotypic variation in its activity may moderate effects of methamphetamine on brain structure and function. This study explored the relationship between CYP2D6 genotype and measures of brain structure and cognition in methamphetamine users. Based on the function of genetic variants, a CYP2D6 activity score was determined in 82 methamphetamine-dependent (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria) and 79 healthy-control participants who completed tests of cognitive function (i.e., attention, memory, and executive function); most were also evaluated with structural magnetic resonance imaging (MRI) (66 methamphetamine-dependent and 52 controls). The relationship between CYP2D6 activity score and whole brain cortical thickness differed by group (interaction p = 0.024), as increasing CYP2D6 activity was associated with thinner cortical thickness in the methamphetamine users (β = -0.254; p = 0.035), but not in control subjects (β = 0.095; p = 0.52). Interactions between CYP2D6 activity and group were nonsignificant for hippocampal volume (ps > 0.05), but both hippocampi showed trends similar to those observed for cortical thickness (negative relationships in methamphetamine users [ps < 0.05], and no relationships in controls [ps > 0.50]). Methamphetamine users had lower cognitive scores than control subjects (p = 0.007), but there was no interaction between CYP2D6 activity score and group on cognition (p > 0.05). Results suggest that CYP2D6 genotypes linked to higher enzymatic activity may confer risk for methamphetamine-induced deficits in brain structure. The behavioral consequences of these effects are unclear and warrant additional investigation.
      Cover page: CYP2D6 genotype may moderate measures of brain structure in methamphetamine users
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2017)
      In the brain, microglia continuously scan the surrounding extracellular space in order to respond to damage or infection by becoming activated and participating in neuroinflammation. When activated, microglia increase the expression of translocator protein (TSPO) 18 kDa, thereby making the TSPO expression a marker for neuroinflammation. We used the radiotracer [11C]DAA1106 (a ligand for TSPO) and positron emission tomography (PET) to determine the effect of smoking on availability of this marker for neuroinflammation. Forty-five participants (30 smokers and 15 non-smokers) completed the study and had usable data. Participants underwent a dynamic PET scanning session with bolus injection of [11C]DAA1106 (with smokers in the satiated state) and blood draws during PET scanning to determine TSPO affinity genotype and plasma nicotine levels. Whole-brain standardized uptake values (SUVs) were determined, and analysis of variance was performed, with group (smoker vs non-smoker) and genotype as factors, thereby controlling for genotype. Smokers and non-smokers differed in whole-brain SUVs (P=0.006) owing to smokers having 16.8% lower values than non-smokers. The groups did not differ in injected radiotracer dose or body weight, which were used to calculate SUV. An inverse association was found between whole-brain SUV and reported cigarettes per day (P<0.05), but no significant relationship was found for plasma nicotine. Thus, smokers have less [11C]DAA1106 binding globally than non-smokers, indicating less microglial activation. Study findings are consistent with much prior research demonstrating that smokers have impaired inflammatory functioning compared with non-smokers and that constituents of tobacco smoke other than nicotine affect inflammatory processes.
        Cover page: Effect of Cigarette Smoking on a Marker for Neuroinflammation: A [11C]DAA1106 Positron Emission Tomography Study
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2018)
        This corrects the article DOI: 10.1038/npp.2017.48.
          Cover page: Erratum: Effect of Cigarette Smoking on a Marker for Neuroinflammation: A [11C]DAA1106 Positron Emission Tomography Study
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2020)

          Background

          Radioligands for the translocator protein (TSPO) 18 kDa have been used with positron emission tomography (PET) to assess neuroinflammation and microglial activation in psychiatric disorders. One study using this approach showed substantial TSPO elevation throughout the brain in chronic methamphetamine users following long-term abstinence (0.5-4 years), but clients typically present for treatment earlier in abstinence.

          Methods

          We used PET with [11C]DAA1106 to compare standardized uptake values (SUVs) as an index of TSPO binding in the brains of methamphetamine-dependent participants who were abstinent for < 6 months (n = 11) and healthy controls (n = 12). We also assayed other typical correlates of Methamphetamine Dependence (e.g., striatal D2-type dopamine receptor deficits, depressed mood, anxiety and impaired emotion regulation).

          Results

          Methamphetamine users exhibited depression (p < 0.0001), anxiety (p = 0.002), difficulties in emotional regulation (p = 0.01), and lower striatal dopamine D2-type receptor availability vs. controls (p = 0.02). SUVs for [11C]DAA1106 were larger in all brain regions of methamphetamine-dependent participants vs. controls, but the effect size was small to medium and not statistically significant.

          Conclusions

          The discrepancy between the lack of significant difference in TSPO binding in early-abstinent methamphetamine users vs. controls in this study and a previous report of elevated binding in longer-abstinent methamphetamine users may reflect methodological differences or limitations of TSPO binding as an index of neuroinflammation. It also seems possible that gliosis increases over time during the first 6 months of abstinence; longitudinal studies could clarify this possibility.
            Cover page: No significant elevation of translocator protein binding in the brains of recently abstinent methamphetamine users
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2018)

            Rationale

            Microglia are the main immune cells in the central nervous system and participate in neuroinflammation. When activated, microglia express increased levels of the translocator protein 18 kDa (TSPO), thereby making TSPO availability a marker for neuroinflammation. Using positron emission tomography (PET) scanning, our group recently demonstrated that smokers in the satiated state had 16.8% less binding of the radiotracer [11C]DAA1106 (a radioligand for TSPO) in the brain than nonsmokers.

            Objectives

            We sought to determine the effect of overnight smoking abstinence on [11C]DAA1106 binding in the brain.

            Methods

            Forty participants (22 smokers and 18 nonsmokers) completed the study (at one of two sites) and had usable data, which included images from a dynamic [11C]DAA1106 PET scanning session (with smokers having been abstinent for 17.9 ± 2.3 h) and a blood sample for TSPO genotyping. Whole brain standardized uptake values (SUVs) were determined, and analysis of variance was performed, with group (overnight abstinent smoker vs. nonsmoker), site, and TSPO genotype as factors, thereby controlling for site and genotype.

            Results

            Overnight abstinent smokers had lower whole brain SUVs (by 15.5 and 17.0% for the two study sites) than nonsmokers (ANCOVA, P = 0.004). The groups did not significantly differ in injected radiotracer dose or body weight, which were used to calculate SUV.

            Conclusions

            These results in overnight abstinent smokers are similar to those in satiated smokers, indicating that chronic cigarette smoking leads to global impairment of microglial activation which persists into early abstinence. Other explanations for study results, such as smoking leading to reduced numbers of microglia or smokers having more rapid metabolism of the radiotracer than nonsmokers, are also possible.
              Cover page: Effect of overnight smoking abstinence on a marker for microglial activation: a [<sup>11</sup>C]DAA1106 positron emission tomography study.
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2020)

              Radioligands for the translocator protein (TSPO) 18 kDa have been used with positron emission tomography (PET) to assess neuroinflammation and microglial activation in psychiatric disorders. One study using this approach showed substantial TSPO elevation throughout the brain in chronic methamphetamine users following long-term abstinence (0.5-4 years), but clients typically present for treatment earlier in abstinence.

              We used PET with [11C]DAA1106 to compare standardized uptake values (SUVs) as an index of TSPO binding in the brains of methamphetamine-dependent participants who were abstinent for < 6 months (n = 11) and healthy controls (n = 12). We also assayed other typical correlates of Methamphetamine Dependence (e.g., striatal D2-type dopamine receptor deficits, depressed mood, anxiety and impaired emotion regulation).

              Methamphetamine users exhibited depression (p < 0.0001), anxiety (p = 0.002), difficulties in emotional regulation (p = 0.01), and lower striatal dopamine D2-type receptor availability vs. controls (p = 0.02). SUVs for [11C]DAA1106 were larger in all brain regions of methamphetamine-dependent participants vs. controls, but the effect size was small to medium and not statistically significant.

              The discrepancy between the lack of significant difference in TSPO binding in early-abstinent methamphetamine users vs. controls in this study and a previous report of elevated binding in longer-abstinent methamphetamine users may reflect methodological differences or limitations of TSPO binding as an index of neuroinflammation. It also seems possible that gliosis increases over time during the first 6 months of abstinence; longitudinal studies could clarify this possibility.

                Cover page: No significant elevation of translocator protein binding in the brains of recently abstinent methamphetamine users.
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