Relative to other substances of abuse (e.g. alcohol, tobacco) the mechanisms which underlie the onset and progression of methamphetamine use disorders (METH) and their consequences (e.g. HIV risk behavior) are unclear. The purpose of this dissertation was to elucidate potential mechanisms using a systems biology and ecological approach in which, genetic, neurocognitive, and behavioral data were examined and explored in the context of METH and HIV. First a synthesis of the current genetic association literature was conducted to provide a systematic and quantitative review of the genetic epidemiology of METH use disorders. Then utilizing results obtained from the synthesis and existing data on 400 adults with and without HIV-infection and/or METH dependence, a series of analyses were undertaken to replicate putative genetic markers for METH dependence as well as to examine and explore genetic, neurocognitive and contextual factors for HIV risk behaviors. All subjects underwent a comprehensive clinical characterization that included: demographic information, standardized medical examination, neurocognitive and psychiatric assessment as well as HIV risk behavior assessment. Available blood samples were used for DNA extraction and genotyping. Synthesis of the literature uncovered 39 genes, of which 18 were found to have a putative genotypic, allelic, and/ or haplotypic association with METH use disorders, predominately in Asian populations. Case-control analysis among a diverse sample of African-Americans, Hispanics, and Caucasians for six of the putative and three novel genes suggested considerable ethnic divergence for METH dependence. Cross-sectional analyses revealed several complex associations between genetic [i.e. catechol-o- methyltransferase (COMT)], neurocognitive (i.e. executive functioning), and contextual (i.e. METH, HIV) factors on HIV risk behavior. Analyses suggested that dependent on a subjects COMT genotype and context, executive functioning and HIV risk behavior profiles can be significantly different, respectively. Findings provide support for further validation of candidate genes for METH dependence reported among Asian populations across other ethnic/ ancestral groups as well as, examination of gene-context (i.e. gene-environment) associations and neurocognitive factors to better understand the complexity of HIV risk behavior

Clinicians still employ a "trial-and-error" approach to optimizing treatment regimens for late-life depression (LLD). With LLD affecting a significant and growing segment of the population, and with only about half of older adults responsive to antidepressant therapy, there is an urgent need for a better treatment paradigm. Pharmacogenetic decision support tools (DSTs), which are emerging technologies that aim to provide clinically actionable information based on a patient's genetic profile, offer a promising solution. Dozens of DSTs have entered the market in the past 15 years, but with varying level of empirical evidence to support their value. In this clinical review, we provide a critical analysis of the peer-reviewed literature on DSTs for major depression management. We then discuss clinical considerations for the use of these tools in treating LLD, including issues related to test interpretation, timing, and patient perspectives. In adult populations, newer generation DSTs show promise for the treatment of major depression. However, there are no primary clinical trials in LLD cohorts. Independent and comparative clinical trials are needed.

Background

Methamphetamine is a major contributor to HIV transmission among men who have sex with men (MSM). Recent studies show that up to one-third of methamphetamine-using MSM (MUMSM) inject the drug. We developed a behavioral intervention for MUMSM to decrease unprotected anal intercourse and increase awareness of parenteral HIV transmission risk. This 6-session (3 in-person, 3 by telephone) modular intervention was designed to be tailored to participants' HIV (+/-) and injection drug user ([IDU] yes/no) status. We present results of formative research used to evaluate the content and to assess feasibility and acceptability of this individual-level HIV risk-reduction intervention.

Setting

HIV research clinic in a high MSM and methamphetamine prevalence neighborhood.

Project

Avoiding Risks from Methamphetamine-Use (ARM-U) is a brief toolbox intervention that allows counselors to select modules that suit a client's individual risk profile and intervention needs employing motivational interviewing and cognitive behavioral theory. We evaluated the format and content of the intervention through focus groups and pre-testing of the entire intervention using volunteers from the target population stratified into four groups (HIV+/IDU, HIV-/IDU, HIV+/non-IDU, HIV-/non-IDU). Four individuals in each stratum were recruited to undergo the intervention and complete a satisfaction survey at the end of each in-person session.

Results

In total, 25 MUMSM attended one of five focus groups. Participants thought all proposed intervention topics were important and could aid in reducing sexual risk behaviors among MUMSM. However, the neurocognitive effects of methamphetamine were reported to be a barrier to practicing safer sex, condom use negotiation or HIV status disclosure. Fifteen (94%) of 16 participants completed all 6 sessions and the satisfaction survey. On average, participants felt the intervention was useful for MUMSM, made them contemplate and move toward behavior change, and would recommend the program to their peers.

Lessons learned

Based on our formative research, we revised the ARM-U intervention to emphasize pre-planning to avoid combining methamphetamine use and sex or develop strategies to avoid sex risk following methamphetamine use. We also increased emphasis on referrals for care and other requested services. Future efficacy trials are needed to evaluate the intervention's ability to reduce HIV-associated risk behaviors.

Introduction

The Val allele of the Val158Met single-nucleotide polymorphism of the catechol-o-methyltransferase gene (COMT) confers greater catabolism of dopamine (DA) in the prefrontal cortex (PFC) than the Met allele. Met/Met homozygotes typically outperform Val-carriers on tests of executive function (EF), perhaps resulting from increased DA bioavailability. Methamphetamine (METH) causes large releases of DA, which is associated with neurotoxicity and executive dysfunction in chronic METH users. We hypothesized that, contrary to its effect in non-METH-using populations, slower DA clearance conferred by Met/Met will relate to worse EF in METH users.

Methods

149 non-Hispanic White men, stratified by METH dependence (METH+/-) and COMT (Val/Val, Val/Met, Met/Met), completed three tests of EF: Wisconsin Card Sorting Test (WCST), Stroop Color-Word Test (Stroop), and Trail Making Test Part B (Trails B). Demographically-adjusted test scores were averaged to create an EF composite T-score. We examined the interaction of METH and COMT on the EF composite and individual test T-scores, controlling for premorbid functioning and alcohol use.

Results

METH group differences in EF were evident only among Met/Met carriers (beta = -9.36, p < .001) but not among Val carriers: Val/Met (beta = -1.38, p = .44) and Val/Val (beta = -4.34, p = .10). These effects were most salient on the WCST.

Conclusions

In the pre-frontal hyperdopaminergic state triggered by methamphetamine, greater DA inactivation conferred by the Val allele may protect against METH-related executive dysfunction, suggesting genetically-driven differences in vulnerability to METH.

Background and objectives

Understanding methamphetamine associated psychotic (MAP) symptom typologies could aid in identifying individuals at risk of progressing to schizophrenia and guide early intervention.

Methods

Latent class analysis (LCA) of psychotic symptoms collected from 40 (n = 40) methamphetamine dependent individuals with a history of psychotic symptoms but no history of a primary psychotic disorder.

Results

Three typologies were identified. In one, persecutory delusions dominated (Type 1), in another persecutory delusions were accompanied by hallucinations (Type 2), and in the third a high frequency of all the assessed hallucinatory and delusional symptoms was observed (Type 3).

Discussion and conclusion

MAP is a heterogeneous syndrome with positive symptom typologies.

Scientific significance

This study represents the first attempt at identifying typologies of MAP and highlights the potential utility of LCA in future large-scale studies.