Increased Prevalence of Metabolic Syndrome in Veterans with PTSD Untreated with Antipsychotic Medications.

Post-Traumatic Stress Disorder (PTSD) is not solely a psychiatric disorder; it also includes significant medical morbidity. Although there is evidence of increased risk of metabolic syndrome (MetS) in PTSD, the interpretation of previous studies is confounded by inclusion of people on antipsychotic medications, which independently cause increased MetS. In this study we investigated whether Veterans with PTSD not treated with antipsychotic medications (n=115) demonstrate increased MetS compared to an age-comparable group of people from the U.S. National Health and Nutrition Examination Survey (NHNES; n=1005). Using standardized criteria (abnormal values in 3 out of the 5 domains of obesity, hypertension, high density lipoprotein, triglyceride and fasting glucose concentrations) we compared the prevalence of MetS across groups. Relative to the NHNES group, a significantly higher proportion of the Veteran PTSD group met criteria for MetS (26.9% vs. 41.7%) with a higher proportion of abnormal values in four out of five MetS domains (excepting glucose). Our results suggest that the elevation of MetS associated with PTSD cannot be fully explained by iatrogenic effects of antipsychotic medication. We suggest that extra attention be devoted to the clinical management of metabolic risk factors for morbidity in patients with PTSD.

Allostatic load and the cannabinoid system: implications for the treatment of physiological abnormalities in post-traumatic stress disorder (PTSD).

It is becoming clear that post-traumatic stress disorder (PTSD) is not simply a psychiatric disorder, but one that involves pervasive physiological impairments as well. These physiological disturbances deserve attention in any attempt at integrative treatment of PTSD that requires a focus beyond the PTSD symptoms themselves. The physiological disturbances in PTSD range over many systems, but a common thread thought to underlie them is that the chronic effects of PTSD involve problems with allostatic control mechanisms that result in an excess in what has been termed "allostatic load" (AL). A pharmacological approach to reducing AL would be valuable, but, because of the large range of physiological issues involved - including metabolic, inflammatory, and cardiovascular systems - it is unclear whether there exists a simple comprehensive way to address the AL landscape. In this paper, we propose that the cannabinoid system may offer just such an approach, and we outline evidence for the potential utility of cannabinoids in reducing many of the chronic physiological abnormalities seen in PTSD which are thought to be related to excess AL.

A quantitative measure of handwriting dysfluency for assessing tardive dyskinesia.

Tardive dyskinesia (TD) is a movement disorder commonly associated with chronic exposure to antidopaminergic medications, which may be in some cases disfiguring and socially disabling. The consensus from a growing body of research on the incidence and prevalence of TD in the modern era of antipsychotics indicates that this disorder has not disappeared continues to challenge the effective management of psychotic symptoms in patients with schizophrenia. A fundamental component in an effective strategy for managing TD is its reliable and accurate assessment. In the present study, we examined the clinical utility of a brief handwriting dysfluency measure for quantifying TD. Digitized samples of handwritten circles and loops were obtained from 62 psychosis patients with or without TD and from 50 healthy subjects. Two measures of dysfluent pen movements were extracted from each vertical pen stroke, including normalized jerk and the number of acceleration peaks. Tardive dyskinesia patients exhibited significantly higher dysfluency scores than non-TD patients and controls. Severity of handwriting movement dysfluency was correlated with Abnormal Involuntary Movement Scale severity ratings for some tasks. The procedure yielded high degrees of test-retest reliability. These results suggest that measures of handwriting movement dysfluency may be particularly useful for objectively evaluating the efficacy of pharmacotherapeutic strategies for treating TD.

Is Post-Traumatic Stress Disorder Associated with Premature Senescence? A Review of the Literature.

OBJECTIVE: Post-traumatic stress disorder (PTSD) has major public health significance. Evidence that PTSD may be associated with premature senescence (early or accelerated aging) would have major implications for quality of life and healthcare policy. We conducted a comprehensive review of published empirical studies relevant to early aging in PTSD. METHOD: Our search included the PubMed, PsycINFO, and PILOTS databases for empirical reports published since the year 2000 relevant to early senescence and PTSD, including: 1) biomarkers of senescence (leukocyte telomere length [LTL] and pro-inflammatory markers), 2) prevalence of senescence-associated medical conditions, and 3) mortality rates. RESULTS: All six studies examining LTL indicated reduced LTL in PTSD (pooled Cohen's d = 0.76). We also found consistent evidence of increased pro-inflammatory markers in PTSD (mean Cohen's ds), including C-reactive protein = 0.18, Interleukin-1 beta = 0.44, Interleukin-6 = 0.78, and tumor necrosis factor alpha = 0.81. The majority of reviewed studies also indicated increased medical comorbidity among several targeted conditions known to be associated with normal aging, including cardiovascular disease, type 2 diabetes mellitus, gastrointestinal ulcer disease, and dementia. We also found seven of 10 studies indicated PTSD to be associated with earlier mortality (average hazard ratio: 1.29). CONCLUSION: In short, evidence from multiple lines of investigation suggests that PTSD may be associated with a phenotype of accelerated senescence. Further research is critical to understand the nature of this association. There may be a need to re-conceptualize PTSD beyond the boundaries of mental illness, and instead as a full systemic disorder.

The clinical challenges of akathisia.

Akathisia is one of the most vexing problems in neuropsychiatry. Although it is one of the most common side effects of antipsychotic medications, it is often difficult to describe by patients, and is difficult to diagnose and treat by practitioners. Akathisia is usually grouped with extrapyramidal movement disorders (ie, movement disorders that originate outside the pyramidal or corticospinal tracts and generally involve the basal ganglia). Yet, it can present as a purely subjective clinical complaint, without overt movement abnormalities. It has been subtyped into acute, subacute, chronic, tardive, withdrawal-related, and "pseudo" forms, although the distinction between many of these is unclear. It is therefore not surprising that akathisia is generally either underdiagnosed or misdiagnosed, which is a serious problem because it can lead to such adverse outcomes as poor adherence to medications, exacerbation of psychiatric symptoms, and, in some cases, aggression, violence, and suicide. In this article, we will attempt to address some of the confusion surrounding the condition, its relationship to other disorders, and differential diagnosis, as well as treatment alternatives.

CogSMART Compensatory Cognitive Training for Traumatic Brain Injury: Effects Over 1 Year.

OBJECTIVE: There are very few evidence-based treatments for individuals with mild to moderate traumatic brain injuries. We developed and tested a 12-week, manualized, compensatory cognitive training intervention, Cognitive Symptom Management and Rehabilitation Therapy (CogSMART), which targeted postconcussive symptom management, prospective memory, attention, learning/memory, and executive functioning. The intervention focused on psychoeducation and compensatory strategies such as calendar use, self-talk, note taking, and a 6-step problem-solving method. SETTING: VA Healthcare System. PARTICIPANTS: A total of 50 Veterans with mild to moderate traumatic brain injuries receiving supported employment. DESIGN: Twelve-month randomized controlled trial with participants assigned to receive CogSMART or additional supported employment sessions for the first 12 weeks. Outcome assessments were administered at baseline and 3, 6, and 12 months. MAIN MEASURES: Assessments measured postconcussive symptoms, neuropsychological performance, functional capacity, psychiatric symptom severity, quality of life, and weeks worked during the 12-month trial. RESULTS: Hierarchical linear modeling analyses using all 4 time points demonstrated significant CogSMART-associated reductions in postconcussive symptoms (r = -0.28, P = .026, d = 0.64) and improvements in prospective memory (r = 0.35, P = .031, d = 0.55) and quality of life (r = 0.34, P = .009, d = 1.0). The groups did not differ on weeks worked during the trial. CONCLUSION: CogSMART has the potential to improve postconcussive symptoms, cognitive performance, and self-rated quality of life in individuals with mild to moderate traumatic brain injuries.

Post-traumatic stress symptoms and adult attachment: a 24-year longitudinal study.

OBJECTIVES: Attachment theory has become a key framework for understanding responses to and consequences of trauma across the life course. We predicted that more severe post-traumatic stress (PTS) symptoms at age 37 years would be associated with insecure attachment at age 55 and with worse PTS symptoms 24 years later at age 61, and that age 55 attachment would mediate the influence of earlier PTS symptoms on later symptoms. DESIGN: Data on PTS self-reported symptoms were available for 975 community-dwelling participants from the longitudinal Vietnam Era Twin Study of Aging at ages 37 and 61 years. At age 55, participants completed the Experiences in Close Relationships Inventory, a measure of adult attachment. RESULTS: PTS symptoms at ages 37 and 61 correlated (r = 0.43; p <0.0001). Multiple mediation models found significant direct effects of age 37 PTS symptoms on age 61 PTS symptoms (ß = 0.26; 95% confidence interval: 0.19-0.33). Anxious and avoidant attachment at age 55 predicted PTS symptoms at age 61 (r = 0.34 and 0.25; ps <0.0001, respectively) and also significantly mediated PTS symptoms over time, showing that insecure attachment increased PTS severity. Participants with higher age 37 PTS symptoms were more likely to have a history of divorce; marital status did not mediate PTS. CONCLUSIONS: Analyses demonstrate the persistence of PTS symptoms from early midlife into early old age. Mediation analyses revealed that one path through which PTS symptoms persisted was indirect: through their influence on attachment insecurity. This study provides insight into ongoing interconnections between psychological and interpersonal responses to stress.

White matter integrity in veterans with mild traumatic brain injury: associations with executive function and loss of consciousness.

OBJECTIVE: We investigated using diffusion tensor imaging (DTI) and the association between white matter integrity and executive function (EF) performance in postacute mild traumatic brain injury (mTBI). In addition, we examined whether injury severity, as measured by loss of consciousness (LOC) versus alterations in consciousness (AOC), is related to white matter microstructural alterations and neuropsychological outcome. PARTICIPANTS: Thirty Iraq and Afghanistan War era veterans with a history of mTBI and 15 healthy veteran control participants. RESULTS: There were no significant overall group differences between control and mTBI participants on DTI measures. However, a subgroup of mTBI participants with EF decrements (n = 13) demonstrated significantly decreased fractional anisotropy of prefrontal white matter, corpus callosum, and cingulum bundle structures compared with mTBI participants without EF decrements (n = 17) and control participants. Participants having mTBI with LOC were more likely to evidence reduced EF performances and disrupted ventral prefrontal white matter integrity when compared with either mTBI participants without LOC or control participants. CONCLUSIONS: Findings suggest that altered white matter integrity contributes to reduced EF in subgroups of veterans with a history of mTBI and that LOC may be a risk factor for reduced EF as well as associated changes to ventral prefrontal white matter.

Pain sensitivity in posttraumatic stress disorder and other anxiety disorders: a preliminary case control study.

BACKGROUND: Despite substantial research on the comorbidity of anxiety disorders including posttraumatic stress disorder (PTSD) and chronic pain, little is known about the mechanisms underlying these conditions that might be potentially similar. Evoked pain sensitivity is one factor that has been associated with several pain conditions which might also have relevance to anxiety disorders and PTSD. The aim of this preliminary study was to examine evoked pain sensitivity in PTSD compared to other anxiety disorders and in control participants. METHOD: The study used a cross-sectional case-control design in which participants completed a battery of questionnaires and structured interview and underwent cold pressor testing. RESULTS: Of 61 total participants, those in the PTSD (n =16) and other anxiety groups (n =12) endorsed significantly higher levels of psychological symptoms and poorer health functioning than control participants (n =33). The linear trend across baseline, threshold, and tolerance pain ratings from the cold pressor task significantly differed between participants with PTSD and the other anxiety and control groups suggesting lower pain sensitivity to a standardized stimulus of pain in individuals with PTSD. CONCLUSIONS: These findings are similar to some of the prior research and suggest that individuals with PTSD may exhibit lower cold pain sensitivity compared to those with other anxiety disorders. There is a need for future research to determine explanatory mechanisms.

The Peritraumatic Behavior Questionnaire: development and initial validation of a new measure for combat-related peritraumatic reactions.

BACKGROUND: Posttraumatic stress disorder (PTSD) is one of the most commonly observed stress-related conditions following combat exposure and its effective prevention is a high health-care priority. Reports of peritraumatic reactions have been shown to be highly associated with PTSD among combat exposed service members. However, existing instruments measuring peritraumatic symptoms were not specifically developed to assess combat-related peritraumatic stress and each demonstrates a different peritraumatic focus. We therefore developed the Peritraumatic Behavior Questionnaire (PBQ), a new military-specific rating scale focused upon the wide range of symptoms suggestive of combat-related peritraumatic distress in actively deployed Service Members. This study describes the development of the PBQ and reports on the psychometric properties of its self-rated version (PBQ-SR). METHODS: 688 Marine infantry service members were retrospectively assessed by the PBQ-SR within the scope of the Marine Resiliency Study after their deployment to war zone. Participants have been additionally assessed by a variety of questionnaires, as well as clinical interviews both pre and post-deployment. RESULTS: The PBQ-SR demonstrated satisfactory internal consistency, convergent and discriminant validity, as well as high correlation with trait dissociation prior to deployment. Component analysis suggested a latent bi-dimensional structure separating a peritraumatic emotional distress and physical awareness factor. The PBQ-SR total score showed high correlation to general anxiety, depression, poorer general health and posttraumatic symptoms after deployment and remained a significant predictor of PTSD severity, after controlling for those measures. The suggested screening cut-off score of 12 points demonstrated satisfactory predictive power. CONCLUSIONS: This study confirms the ability of the PBQ-SR to unify the underlying peritraumatic symptom dimensions and reliably assess combat-related peritraumatic reaction as a general construct. The PBQ-SR demonstrated promise as a potential standard screening measure in military clinical practice, while It's predictive power should be established in prospective studies.

Blood-based gene-expression predictors of PTSD risk and resilience among deployed marines: a pilot study.

Susceptibility to PTSD is determined by both genes and environment. Similarly, gene-expression levels in peripheral blood are influenced by both genes and environment, and expression levels of many genes show good correspondence between peripheral blood and brain. Therefore, our objectives were to test the following hypotheses: (1) pre-trauma expression levels of a gene subset (particularly immune-system genes) in peripheral blood would differ between trauma-exposed Marines who later developed PTSD and those who did not; (2) a predictive biomarker panel of the eventual emergence of PTSD among high-risk individuals could be developed based on gene expression in readily assessable peripheral blood cells; and (3) a predictive panel based on expression of individual exons would surpass the accuracy of a model based on expression of full-length gene transcripts. Gene-expression levels were assayed in peripheral blood samples from 50 U.S. Marines (25 eventual PTSD cases and 25 non-PTSD comparison subjects) prior to their deployment overseas to war-zones in Iraq or Afghanistan. The panel of biomarkers dysregulated in peripheral blood cells of eventual PTSD cases prior to deployment was significantly enriched for immune genes, achieved 70% prediction accuracy in an independent sample based on the expression of 23 full-length transcripts, and attained 80% accuracy in an independent sample based on the expression of one exon from each of five genes. If the observed profiles of pre-deployment mRNA-expression in eventual PTSD cases can be further refined and replicated, they could suggest avenues for early intervention and prevention among individuals at high risk for trauma exposure.

Gene-environment interaction of ApoE genotype and combat exposure on PTSD.

Factors determining who develops PTSD following trauma are not well understood. The €4 allele of the apolipoprotein E (apoE) gene is associated with dementia and unfavorable outcome following brain insult. PTSD is also associated with dementia. Given evidence that psychological trauma adversely affects the brain, we hypothesized that the apoE genotype moderates effects of psychological trauma on PTSD pathogenesis. To investigate the moderation of the relationship between PTSD symptoms and combat exposure, we used 172 participants with combat trauma sustained during the Vietnam War. PTSD symptoms were the dependent variable and number of combat experiences, apoE genotype, and the combat experiences × apoE genotype interaction were predictors. We also examined the outcome of a diagnosis of PTSD (n = 39) versus no PTSD diagnosis (n = 131). The combat × apoE genotype interaction was significant for both PTSD symptoms (P = .014) and PTSD diagnosis (P = .009). ApoE genotype moderates the relationship between combat exposure and PTSD symptoms. Although the pathophysiology of PTSD is not well understood, the €4 allele is related to reduced resilience of the brain to insult. Our results are consistent with the €4 allele influencing the effects of psychological trauma on the brain, thereby affecting the risk of PTSD.

Metabolic syndrome: relative risk associated with post-traumatic stress disorder (PTSD) severity and antipsychotic medication use.

BACKGROUND: In recent years, numerous lines of converging evidence have revealed an association between post-traumatic stress disorder (PTSD) and impaired physical health outcomes, including cardiovascular disease and metabolic syndrome. Although these findings have been interpreted as indicating a direct association of PTSD with metabolic syndrome and obesity, previous studies have not addressed the important confound of antipsychotic drug usage in this population. Second generation antipsychotic medications themselves are associated with metabolic syndrome and obesity, and it is unclear whether the common utilization of these drugs in PTSD may account for some if not all of the observed metabolic problems. OBJECTIVE: The present study examined the relative contributions of PTSD severity and use of antipsychotic medications to risk of metabolic syndrome among veterans. METHOD: Cross-sectional clinical data, including five factors representing metabolic syndrome, psychiatric diagnoses, and medications were gathered from 253 veterans enrolling in mental health services. We used a logistic regression model to measure the relative association of antipsychotic medication use and PTSD severity on risk of metabolic syndrome. RESULTS: We found that antipsychotic medication usage was not uniquely associated with elevated risk of metabolic syndrome (Wald = 0.30, ns) when PTSD severity and other sociodemographic, psychiatric, and behavioral variables were accounted for. Furthermore, PTSD severity continued to be a significant and unique predictor of risk for metabolic syndrome (Wald = 4.04, p < 0.05). CONCLUSIONS: These findings suggest that chronic and moderately severe PTSD, independent of antipsychotic medications, is associated with increased risk of metabolic syndrome.

Effects of anxiolytic treatment on potentiated startle during aversive image anticipation.

OBJECTIVE: Heightened anticipation of future events has been characterized as a feature of certain anxiety disorders. In functional magnetic resonance imaging studies, anticipation of fearful/threatening images has been shown to robustly activate the insular cortex and amygdala in healthy subjects, in subjects with high trait anxiety, and in some with anxiety disorders. Blood oxygenation level dependent activation in response to negative image anticipation is also sensitive to anxiolytic treatment, suggesting that image anticipation probes anxiety systems. It is not clear, however, if behavioral responses to image anticipation are also sensitive to anxiolytics. This study tested the hypothesis that anxiety behaviors during anticipation of negative images are sensitive to anxiolytic treatment. METHOD: This study examined the effects of alprazolam and pregabalin treatment on potentiated startle during affective image anticipation. RESULTS: There was an effect of anticipation type (negative versus neutral versus positive) on startle reactivity and subjective ratings, suggesting that the task was effective in assaying negative anticipatory arousal. Both treatments significantly reduced overall startle magnitude. However, neither treatment specifically affected potentiated startle during aversive anticipation. CONCLUSION: These data suggest that potentiated startle in response to anticipation of aversive images is not sensitive to anxiolytic treatments in a healthy population, limiting its use as a predictive model of anxiolytic activity. This article is a US Government work and is in the public domain in the USA.

Loneliness in Posttraumatic Stress Disorder: A Neglected Factor in Accelerated Aging?

Prior research suggests that people with Posttraumatic Stress Disorder (PTSD) may experience a form of accelerated biological aging. In other populations, loneliness has been shown to elevate risk for many of the same components of accelerated biological aging, and other deleterious outcomes, as seen in people with PTSD. Although standard diagnostic criteria for PTSD include "feelings of detachment or estrangement from others", the relationship of such feelings to the concept of loneliness remains uncertain, in par potentially due to a failure to distinguish between loneliness versus objective social isolation. In order to catalyze wider research attention to loneliness in PTSD, and the potential contribution to accelerated biological aging, the present paper provides three components: (1) a conceptual overview of the relevant constructs and potential interrelationships, (2) a review of the limited extant empirical literature, and (3) suggested directions for future research. The existing empirical literature is too small to support many definitive conclusions, but there is evidence of an association between loneliness and symptoms of PTSD. The nature of this association may be complex, and the causal direction(s) uncertain. Guided by the conceptual overview and review of existing literature, we also highlight key areas for further research. The ultimate goal of this line of work is to elucidate mechanisms underlying any link between loneliness and accelerated aging in PTSD, and to develop, validate, and refine prevention and treatment efforts.

Handwriting movement kinematics for quantifying extrapyramidal side effects in patients treated with atypical antipsychotics.

Ongoing monitoring of neuroleptic-induced extrapyramidal side effects (EPS) is important to maximize treatment outcome, improve medication adherence and reduce re-hospitalization. Traditional approaches for assessing EPS such as Parkinsonism, tardive akathisia, or dyskinesia rely upon clinical ratings. However, these observer-based EPS severity ratings can be unreliable and are subject to examiner bias. In contrast, quantitative instrumental methods are less subject to bias. Most instrumental methods have only limited clinical utility because of their complexity and costs. This paper describes an easy-to-use instrumental approach based on handwriting movements for quantifying EPS. Here, we present findings from psychiatric patients treated with atypical (second generation) antipsychotics. The handwriting task consisted of a sentence written several times within a 2 cm vertical boundary at a comfortable speed using an inkless pen and digitizing tablet. Kinematic variables including movement duration, peak vertical velocity and the number of acceleration peaks, and average normalized jerk (a measure of smoothness) for each up or down stroke and their submovements were analyzed. Results from 59 psychosis patients and 46 healthy comparison subjects revealed significant slowing and dysfluency in patients compared to controls. We observed differences across medications and daily dose. These findings support the ecological validity of handwriting movement analysis as an objective behavioral biomarker for quantifying the effects of antipsychotic medication and dose on the motor system.

Preliminary evidence of ubiquitin proteasome system dysregulation in schizophrenia and bipolar disorder: convergent pathway analysis findings from two independent samples.

Schizophrenia (SCZ) and bipolar disorder (BPD) are polygenic disorders with many genes contributing to their etiologies. The aim of this investigation was to search for dysregulated molecular and cellular pathways for these disorders as well as psychosis. We conducted a blood-based microarray investigation in two independent samples with SCZ and BPD from San Diego (SCZ = 13, BPD = 9, control = 8) and Taiwan (SCZ = 11, BPD = 14, control = 16). Diagnostic groups were compared to controls, and subjects with a history of psychosis [PSYCH(+): San Diego (n = 6), Taiwan (n = 14)] were compared to subjects without such history [PSYCH(-): San Diego (n = 11), Taiwan (n = 14)]. Analyses of covariance comparing mean expression levels on a gene-by-gene basis were conducted to generate the top 100 significantly dysregulated gene lists for both samples by each diagnostic group. Gene lists were imported into Ingenuity Pathway Analysis (IPA) software. Results showed the ubiquitin proteasome pathway (UPS) was listed in the top ten canonical pathways for BPD and psychosis diagnostic groups across both samples with a considerably low likelihood of a chance occurrence (P = 0.001). No overlap in dysregulated genes populating these pathways was observed between the two independent samples. Findings provide preliminary evidence of UPS dysregulation in BPD and psychosis as well as support further investigation of the UPS and other molecular and cellular pathways for potential biomarkers for SCZ, BPD, and/or psychosis.

The nature of bradykinesia in schizophrenia treated with antipsychotics.

Recognizing drug-induced parkinsonian bradykinesia in psychosis patients can be challenging due to overlapping presentation with psychomotor slowing associated with depression, negative symptoms, or cognitive disturbances. In this study, we apply prior findings on the pathophysiology of bradykinesia in Parkinson's disease to gain an understanding of motor slowing in psychosis patients. Handwriting movements from 57 healthy participants and 70 psychosis patients were recorded on a digitizing tablet. Temporal and kinematic features were extracted from handwritten loops and circles. An independent objective measure based on peak velocity for circles written at maximum speed was used to classify patients as bradykinetic. Using a statistical cut-point derived from normative data, 64% of the patients met criterion for bradykinesia compared with 46% using a conventional observer-based severity rating scale. Bradykinetic patients produced handwriting movements with longer stroke durations, smaller amplitudes and lower peak velocities compared with non-bradykinetic patients. Thirty-six percent of the pen strokes produced by the bradykinetic patients were non-ballistic compare with 20% for the non-bradykinetic patients. The proportion of nonballistic movements observed in handwriting was unrelated to current antipsychotic dose, severity of negative psychosis or depression. The ease-of-use and standardization of a tablet-based approach to quantifying parkinsonian bradykinesia can aid in diagnosing parkinsonian bradykinesia in patients treated with antipsychotics.

Aging and Trauma: Post Traumatic Stress Disorder Among Korean War Veterans.

Having experienced posttraumatic stress disorder 30 years prior to its recognition as a formal disorder, Korean War veterans are now an aging population that requires unique clinical management.

Asymmetry in scientific method and limits to cross-disciplinary dialogue: toward a shared language and science policy in pharmacogenomics and human disease genetics.

Pharmacogenomics is a hybrid field of experimental science at the intersection of human disease genetics and clinical pharmacology sharing applications of the new genomic technologies. But this hybrid field is not yet stable or fully integrated, nor is science policy in pharmacogenomics fully equipped to resolve the challenges of this emerging hybrid field. The disciplines of human disease genetics and clinical pharmacology contain significant differences in their scientific practices. Whereas clinical pharmacology originates as an experimental science, human disease genetics is primarily observational in nature. The result is a significant asymmetry in scientific method that can differentially impact the degree to which gene-environment interactions are discerned and, by extension, the study sample size required in each discipline. Because the number of subjects enrolled in observational genetic studies of diseases is characteristically viewed as an important criterion of scientific validity and reliability, failure to recognize discipline-specific requirements for sample size may lead to inappropriate dismissal or silencing of meritorious, although smaller-scale, craft-based pharmacogenomic investigations using an experimental study design. Importantly, the recognition that pharmacogenomics is an experimental science creates an avenue for systematic policy response to the ethical imperative to prospectively pursue genetically customized therapies before regulatory approval of pharmaceuticals. To this end, we discuss the critical role of interdisciplinary engagement between medical sciences, policy, and social science. We emphasize the need for development of shared standards across scientific, methodologic, and socioethical epistemologic divides in the hybrid field of pharmacogenomics to best serve the interests of public health.