In closing, the present study found drinking behaviors did not significantly mediate the effect of pharmacotherapy on smoking behaviors across the span of 6 months in a sample of heavy drinking smokers engaged in a treatment tailored to promote smoking cessation and drinking reduction. While the main results of the trial showed compelling quit rates and superiority of varenicline plus placebo, compared to varenicline plus naltrexone, the study adds to the importance of targeting smoking and drinking concomitantly. The main findings for the drinking outcome showed a modest superiority of varenicline plus naltrexone on reductions in drinks per drinking day, compared to varenicline plus placebo. Since the main trial showed a complex picture with drinking and smoking results lacking alignment, it is perhaps unsurprising that drinking did not mediate medication effects on smoking. Nevertheless, smoking and drinking behaviors remained intertwined across the trial, primarily at the cross sectional level of analysis. Among participants engaged in smoking cessation and drinking reduction, our results generally confirmed the previous findings that smoking and drinking are intertwined and remain so throughout treatment. As such the concurrent use of alcohol and cigarettes remains a critical clinical target with the potential to result in dramatic improvements to health outcomes with successful smoking cessation and drinking reduction. The dissertation project examined both etiology and treatment of the unique subgroup of heavy drinking smokers.
Etiology of heavy drinking smokers was examined from a behavioral economics framework as one way in which to demonstrate the bidirectional nature of co-use, as well as nuanced complexities in the ways these substances exert cross substance effects . The results made salient how behavioral economic indices may be sensitive to cross-substance relationships. They also further explained the bidirectional relationship between cigarettes and alcohol,indoor grow cannabis showing that such relationships are asymmetrically stronger for smoking variables affecting alcohol demand, not the other way around. Treatment was examined through Chapter 2 and Chapter 3 , utilizing data drawn from the RCT described above. The translation of basic science and experimental pharmacology findings to clinical samples is imperative to elucidate our understanding the role of relevant biological variables such as sex hormones, and to further understand the mechanisms of action underlying pharmacological treatment response on clinical outcomes. Recent findings implicating menstrual cycle phase with smoking behavior and clinical responses to naltrexone have emerged from experimental pharmacology studies. However, these results have not been consistently extended to clinical trials. While our results did not show an effect of the ratio of P4/E2 on smoking outcomes, we did observe an effect of P4/E2 ratio on the drinking outcome of percent days abstinent. These findings are important as they underscore how sex hormones offer important information above and beyond comparing groups on the bases of sex. For Chapter 3, while our results did not reveal drinking outcomes to mediate the relationship between medication condition and smoking outcomes, we did see a consistent pattern throughout active medication phase, and follow-up, where greater drinking and smoking is consistently associated with greater use of the respective substances. These findings call attention to how the relationship between drinking and smoking can be maintained throughout a 6-month clinical trial and furthers the need for the development of treatment options that can target both alcohol and cigarette use in heavy drinking smokers.
Together, these studies use a translation framework that combines pharmacology, experimental psychology, and biomarkers of sex differences in order to address the clinical implications of the co-use of alcohol and cigarettes. These studies advance a precision medicine approach whereby the complimentary between smoking and drinking can be clinically targeted. These studies position the candidate to have a unique and impactful program of research drawing from experimental psychopharmacology, sex differences, advanced data analytic methods, and a patient-centered clinical framework. Proper adherence to combination antiretroviral medication therapy is critical for improving health outcomes in HIV . However, it is estimated that less than 40% of HIV+ individuals are retained in long-term healthcare management and only about one-quarter are virally suppressed in the U.S. . Further, approximately half of individuals prescribed antiretroviral medications do not fully adhere to their regimen . Suboptimal cART adherence is associated with increased viremia, immune suppression, increased risk of HIV transmission, and mortality . Numerous factors appear to be contributing to suboptimal cART adherence, including psychiatric comorbidities , lack of social support, severity of antiretroviral side effects, beliefs about self-efficacy and neurocognitive dysfunction . With regard to the latter, HIV-associated neurocognitive deficits and cART non-adherence appear to have a cyclical relationship; that is, neurocognitive deficits can interfere with medication taking behaviors , which in turn can accelerate disease progression and further impair neurocognitive functioning . The historic complexity of combination antiretroviral therapies may also impose an undue burden on cognitive abilities necessary for adherence . The medications comprising a cART regimen may involve differing dosages and/or administration schedules, which could increase the risk of errors that negatively impact overall adherence, particularly among individuals with neurocognitive difficulties. Although the pill burden of cART is on a downward trajectory, polypharmacy remains common and these challenges are important given that cART is the gold standard for HIV treatment in the United States.
Additionally, the prevalence of HIV associated neurocognitive disorders may have even risen slightly in the cART era, with approximately 50% of the population affected . The elevated rates of HAND and domain-based impairment may be due to increasing lifespans resultant from high cART efficacy, leading to longer exposure to both the presence of virus as well as potentially toxic long-term effects of the drug regimens, combined with comorbid processes such as cognitive aging . While HIV-associated neurocognitive deficits can be observed in a variety of neurocognitive domains, the prevalence of impairment in higher-order neurocognitive abilities,curing cannabis such as episodic memory in particular, are higher . In this study we therefore focus our attention on the role of episodic memory deficits in cART non-adherence. HIV-associated neural injury in frontal and temporal systems affect multiple aspects of episodic memory , including traditional retrospective memory for word lists, designs, and passages, as well as prospective, source, and temporal order memory . The profile of HIV-associated episodic memory deficits is heterogeneous , with prior studies showing evidence that numerous specific memory processes may be disrupted, including learning/acquisition, storage/consolidation, and retrieval . Anywhere from 20 to 40% of HIV+ individuals exhibit a primary retrieval profile of memory deficits consistent with injury to fronto-striato-thalamo-cortical circuits. This retrieval profile is characterized by difficulties in bringing previously stored information into conscious awareness and is evidenced by deficits in free recall of information that are ameliorated when structured retrieval cues are provided . A retrieval profile, which is sometimes referred to as a mixed encoding/retrieval profile, can suggest that an individual only partially encodes the target information. This is because stimuli that were processed only in part are difficult to spontaneously recall in their entirety, but may be accurately recognized when presented. HIV-associated deficits in learning and memory have been linked to poorer everyday functioning, including medication management skills and cART non-adherence. Deficits in acquisition and delayed free recall as a global composite index have been consistently associated with poor performance on laboratory-based medication management tasks across varying types of stimuli . Among the two studies that we found examining specific memory components in the context of adherence, measures of delayed free recall were more consistently associated with medication adherence , whereas indices of initial learning show more variable associations.
Yet the specificity of such delayed recall deficits is difficult to determine, as they may be a consequence of problems with encoding, forgetting, and/or retrieval. Thus, while learning and memory are consistently associated with medication management in the laboratory and daily life, little is known about the specific profile that may be driving these relationships. Identification of such profiles at the levels of both group data and individual participants is important in order to enhance the clinical identification of persons at risk for non-adherence and develop tailored compensatory mnemonic approaches to improve adherence. To that end, Wright and colleagues applied the item specific deficit approach , an item analytic method, to study the association between cART adherence and word list encoding, consolidation, and retrieval as measured by the California Verbal Learning Test in 75 HIV+ participants. The ISDA indices were developed as a novel method for categorizing encoding, consolidation and retrieval deficits. The ISDA encoding index is constructed by summing the number of items recalled in less than three of the five learning trials, the ISDA consolidation index reflects the number of items recalled during the learning trials but not recalled again during any of the recall trials , and retrieval deficits are indexed by the number of learned items recalled inconsistently across short- and long-delay trials. To control for potential group differences in learning, the consolidation and retrieval indices are each divided by the total words recalled at least once during the learning trials. When using the ISDA Wright and colleagues found that, compared to healthy adults, HIV+ individuals demonstrated poorer performance on the CVLT regardless of their level of antiretroviral adherence. Additionally, while both HIV+ groups demonstrated similar ISDA encoding deficits, only non-adherers demonstrated ISDA retrieval deficits compared to HIV− participants. Additionally, retrieval abilities, as measured by the ISDA indices, accounted for a greater proportion of variance in long-delay free recall performance for poor adherers than for good adherers. While the study conducted by Wright and colleagues provided initial evidence of an association between retrieval deficits and suboptimal adherence in HIV, no studies have evaluated the association between suboptimal adherence and traditional list learning profiles that also incorporate retention and recognition performance as is commonly done in clinical research and practice. At the group level, such profile-based approaches have a long tradition of utility in distinguishing between different neuropsychological disorders. For example, retrieval deficits in the context of significantly improved recognition are commonly associated with “subcortical” dementias . “Cortical” dementias , on the other hand, are sometimes differentiated by rapid forgetting, minimal improvement on recognition, and high rates of cued recall intrusions . Our approach here is to employ those same cognitive psychology approaches of learning and memory profile distinctions to better understand the cognitive architecture of non-adherence. To further enhance the clinical relevance of this group-level analytic approach, we also propose to classify individuals’ profiles as reflective of problems with encoding versus retrieval using an established data-based algorithm that has shown utility differentiating traditionally cortical versus subcortical diseases . This algorithm-based individual profile approach has proven to be a worthwhile complement to group-based analyses by allowing for clinically-relevant classification accuracy data and demonstrating the heterogeneity of profiles within these traditionally “cortical” and “subcortical” groups. To our knowledge, this would be the first study to apply this algorithm-based memory profile classification of individuals to understand an important everyday functioning outcome . Further, no study thus far has evaluated the HIV+ memory deficit profiles associated with non-adherence while using different types of verbal stimuli . The format in which information is presented may have a direct impact on memory performance, particularly in the context of medication management. For example, multiple studies have reported improved medication adherence when traditional prescriptions were enhanced with more descriptive instructions about the medication regimen instead of simply listing the information . The current study seeks to expand upon previous research to determine the associations between different episodic memory profiles and antiretroviral non-adherence by utilizing traditional CVLT scoring methods with the inclusion of retention and recognition indices and a concurrent measure of passage recall . In addition to standard group-level analyses of these clinical memory tasks, we also endeavored to look at individual profiles of word list learning as a risk factor for non-adherence using a previously established algorithm for classifying normal, encoding and retrieval profiles. Based on the literature reviewed above, we expect that antiretroviral non-adherence will be associated with a mixed encoding/retrieval profile. These associations may be particularly pronounced on word lists versus story memory given the former’s greater reliance on executive processes , such as strategic encoding, which is reliably impaired in HIV+ individuals and has been strongly associated with non-adherence .The study sample was comprised of 202 HIV+ participants recruited from the general San Diego area . The study was approved by the University of California, San Diego’s Human Research Protections Program.