Frequency of the Dopamine Receptor D3 (rs6280) vs. Opioid Receptor µ1 (rs1799971) Polymorphic Risk Alleles in Patients with Opioid Use Disorder: A Preponderance of Dopaminergic Mechanisms?

While opioids are a powerful class of drugs that inhibit transmission of pain signals, their use is tarnished by the current epidemic of opioid use disorder (OUD) and overdose deaths. Notwithstanding published reports, there remain gaps in our knowledge of opioid receptor mechanisms and their role in opioid seeking behavior. Thus, novel insights into molecular, neurogenetic and neuropharmacological bases of OUD are needed. We propose that an addictive endophenotype may not be entirely specific to the drug of choice but rather may be generalizable to altered brain reward circuits impacting net mesocorticolimbic dopamine release. We suggest that genetic or epigenetic alterations across dopaminergic reward systems lead to uncontrollable self-administration of opioids and other drugs. For instance, diminished availability via knockout of dopamine D3 receptor (DRD3) increases vulnerability to opioids. Building upon this concept via the use of a sophisticated polymorphic risk analysis in a human cohort of chronic opioid users, we found evidence for a higher frequency of polymorphic DRD3 risk allele (rs6280) than opioid receptor µ1 (rs1799971). In conclusion, while opioidergic mechanisms are involved in OUD, dopamine-related receptors may have primary influence on opioid-seeking behavior in African Americans. These findings suggest OUD-targeted novel and improved neuropharmacological therapies may require focus on DRD3-mediated regulation of dopaminergic homeostasis.

PTSD treatment of African American adults in primary care: the gap between current practice and evidence-based treatment guidelines.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a common, potentially disabling, underdiagnosed, and under-treated illness. Primary care physicians assume a critical role in the diagnosis, treatment, and referral of African Americans with PTSD since mental health access is limited for this population. This study is an examination of PTSD treatment of African Americans in the primary care setting. Actual treatment provision is contrasted with existing evidence-based PTSD treatment guidelines. METHOD: Researchers screened 738 consenting, mostly African American, adults in 4 academically affiliated primary care offices for both trauma exposure and mental health symptoms, including PTSD. RESULTS: Employing criteria from the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) (DSM-IV), investigators diagnosed 91 of the participants with current PTSD using the Structured Clinical Interview for DSM and the clinician-administered of PTSD Scale for DSM-IV. Treatment statistics include: 69.2% (n=63) had never received treatment from a mental health provider: 18.6% (n=17) were currently seeing a mental health practitioner; nearly half (47.9%, n=24) of a subsample had never discussed traumatic event exposure or mental health symptoms with their primary care doctor; 32% (n=29) were prescribed psychotropic medication and only 18.6% (n=17) were participating in any form of psychotherapy. Concurrent psychiatric disorders were found in 46.2% (n = 42) of the participants with PTSD. CONCLUSION: Most African American adult primary care patients with PTSD were either undiagnosed or undertreated in this inner-city setting. These results demonstrate a clear need to improve screening and treatment services. Both individual (provider and patient) and system-based changes will be required to meet the demonstrated clinical need.

Serotonin polymorphisms and posttraumatic stress disorder in a trauma exposed African American population.

BACKGROUND: Genetic polymorphisms that influence serotonin (5-hydroxytryptamine, 5HT) neurotransmission are candidates for contributing to susceptibility to posttraumatic stress disorder (PTSD). The objective of our study was to determine if a variable length polymorphism for the promoter regions of the 5HT transporter (5HTTLPR), and/or a substitution polymorphism in the promoter region for the 5HT2A receptor, would be associated with PTSD in a trauma exposed population of adult African-Americans. METHODS: Using a case control design, 118 participants recruited from the primary care clinics and the campus of a historically black university who met inclusion criteria including trauma exposure provided blood samples for genomic DNA. PTSD criteria were determined by the Clinician Assessment of PTSD Scale (CAPS) and criteria for other psychiatric disorders by the Structured Clinical Interview for DSM-IV (SCID). 5HTTLPR and 5HT2A-1438A/G were genotyped using established methods. Associations of genotypes with lifetime PTSD, and models testing associations of allele "dose", were analyzed. RESULTS: Fifty-five (47%) participants met lifetime criteria for PTSD and 26 (22%) met criteria for (mostly comorbid) major depression. The 5HT2A (lower expressing) G allele was significantly associated with PTSD. We did not find significant associations with 5HTTLPR. CONCLUSIONS: Our findings suggest a relationship between genetic variation in the 5HT2A promoter region and PTSD.

Trauma, resilience, and recovery in a high-risk African-American population.

OBJECTIVE: Despite increased risk for psychiatric disorders after trauma exposure, many people are able to adapt with minimal life disruption, and others eventually recover after a symptomatic period. This study examined psychosocial factors associated with resilience and recovery from psychiatric disorders in a high-risk sample of African American adults exposed to a range of severe traumas, who participated in structured diagnostic interviews. METHOD: The sample included 259 patients exposed to at least one severe traumatic event, recruited from primary care offices at Howard University and administered the Structured Clinical Interview for DSM-IV Axis I disorders. Multinomial logistic regression was used to identify potential psychosocial factors associated with resilience and recovery, including purpose in life, mastery, and coping strategies. RESULTS: Forty-seven patients had no lifetime psychiatric disorders (resilient), 85 met criteria for at least one past DSM-IV disorder but no current disorders (recovered), and 127 met criteria for at least one current DSM-IV disorder (currently ill). The resilient group was characterized by a significantly lower lifetime trauma load. Female gender was predictive of currently ill status. In the final model, purpose in life emerged as a key factor associated with both resilience and recovery, and mastery was also significantly associated with recovery. CONCLUSIONS: The identification of psychosocial factors associated with resistance to severe trauma can inform future studies of preventive and treatment interventions for high-risk populations. Further study is needed to determine which psychosocial factors are consistently associated with resilience and to what extent they can be modified through clinical intervention.

Sleep paralysis and trauma, psychiatric symptoms and disorders in an adult African American population attending primary medical care.

The occurrence of sleep paralysis (SP) absent narcolepsy appears to not be uncommon in African Americans and probably other non-European groups. Prior research has linked SP to trauma and psychiatric disorders and suggested a specific relationship to panic disorder in African Americans. The objective of our study was to evaluate relationships of SP with trauma, concurrent psychiatric symptoms and lifetime psychiatric diagnoses in an adult African American population recruited from primary care. Cross sectional study with surveys and diagnostic interviews; Patients attending primary care clinics filled out a survey that determined the 6 month prevalence and associated features of SP, a panic disorder screen, the self-rated Hamilton Depression Scale, and an inventory of trauma exposure. A subset of trauma-exposed participants (N = 142) received comprehensive diagnostic interviews that incorporated the Structured Clinical Interview for DSM-IV and the Clinician Assessed PTSD Scale. Four hundred and forty-one adults participated (mean age-40.0 SD = 13.3, 68% female, 95% African American). Fourteen percent endorsed recent SP. In approximately 1/3 of those with SP, episodes also featured panic symptoms. SP was strongly associated with trauma history, and concurrent anxiety and mood symptoms. SP was not associated with specific psychiatric disorders other than lifetime (but not current) alcohol or substance use disorders. Our findings suggest that SP is not uncommon in adult African Americans and is associated with trauma and concurrent distress but not with a specific psychiatric diagnosis.

Diagnosing bipolar disorder in trauma exposed primary care patients.

OBJECTIVES: Bipolar disorder (BD) is often under-recognized in non-psychiatric settings, especially in African Americans. The Mood Disorder Questionnaire (MDQ) is a screening instrument proposed to show adequate sensitivity and specificity for bipolar spectrum disorders. The current study is an examination of the usefulness of this instrument in a trauma exposed subgroup of mainly African American patients attending primary care clinics. METHODS: The sample is a part of a larger study exploring traumatic stress exposure and psychopathology. Consenting patients in 3 academically affiliated primary care clinics were asked to complete the MDQ. Ninety percent of the participants were African American. Diagnostic performance was determined in a trauma exposed subgroup by employing the Structured Clinical Interview for DSM-IV (SCID) as a gold standard. RESULTS: Of the total group of 579 participants, 178 (30.7%) screened positive for BD along with 77 (33.7%) of the 228 trauma exposed subjects who were SCID interviewed. Only 13 (27%) of the MDQ positives met SCID criteria for BD and were true positives. The sensitivity was 61.9% and the specificity was 69%, with a positive predictive value of 16.8% and a negative predictive value of 94.7%. CONCLUSIONS: The MDQ was found to have low specificity in a predominately African American group of trauma exposed patients attending primary care.

Trauma exposure, posttraumatic stress disorder and depression in an African-American primary care population.

OBJECTIVE: Trauma exposure is high in African Americans who live in stressful urban environments. Posttraumatic stress disorder (PTSD) and depression are common outcomes of trauma exposure and are understudied in African Americans. African Americans are more likely to seek treatment for psychiatric disorders in a primary care setting. Our study evaluated trauma exposure, PTSD and major depression in African Americans attending primary care offices. METHOD: Six-hundred-seventeen patients (96% African Americans) were surveyed for trauma exposure in the waiting rooms of four primary care offices. Those patients reporting significant traumatic events were invited to a research interview. Of the 403 patients with trauma exposure, 279 participated. RESULTS: Of the 617 participants, 65% reported > or = 1 clearly traumatic event. The most common exposures were transportation accidents (42%), sudden unexpected death of a loved one (39%), physical assault (30%), assault with a weapon (29%) and sexual assault (25%). Lifetime prevalence of PTSD and a major depressive episode (MDE) among those with trauma exposure (n=279) was 51% and 35%, respectively. The percent of lifetime PTSD cases (n=142) with comorbid MDE was 46%. Lifetime PTSD and MDE in the trauma-exposed population were approximately twice as common in females than males, whereas current PTSD rates were similar. CONCLUSIONS: Our rate of PTSD (approximately 33% of those screened) exceeds estimates for the general population. Rates of MDE comorbid with PTSD were comparable to other studies. These findings suggest the importance of screening African Americans for PTSD, in addition to depression, in the primary care setting.

An overview of posttraumatic stress disorder in African Americans.

While several studies have found high rates of trauma exposure there is limited information on posttraumatic stress disorder (PTSD) and its relationship to depression in the African American population. The prevalence and/or expression of psychiatric disorders can differ between racial/ethnic groups. The authors review literature addressing trauma exposure, prevalence, and expression of PTSD in the African American population. Risk factors that may be of specific significance to the development of PTSD in African Americans are also reviewed. Additionally, treatment issues and potential directions for future research of PTSD in the African American population are discussed.

Sympathoneural and adrenomedullary functional effects of alpha2C-adrenoreceptor gene polymorphism in healthy humans.

OBJECTIVES: alpha2-Adrenoreceptors restrain sympathetic nervous outflows and inhibit release of noradrenaline from sympathetic nerves. In-frame deletion of the alpha2C-adrenoreceptor subtype (alpha2CDel322-325) increases the risk of congestive heart failure. Increased delivery of catecholamines to cardiovascular receptors might explain this increased risk. METHODS: Twenty-nine healthy African-Americans genotyped for alpha2-adrenoreceptor subtype polymorphisms underwent 3H-noradrenaline and 3H-adrenaline intravenous infusion and arterial blood sampling for measurements of rates of entry of endogenous noradrenaline and adrenaline into arterial plasma (total body spillovers) by the tracer dilution technique. Eleven subjects were homozygotes for the alpha2CDel322-325 polymorphism, nine heterozygotes, and nine non-carriers. Subjects were studied during supine rest and during and after i.v. infusion of the alpha2-adrenoreceptor antagonist, yohimbine. RESULTS: At rest, homozygotes for the alpha2CDel322-325 polymorphism had higher total body noradrenaline spillover than did heterozygotes (t=2.90, df=18, P=0.023) or non-carriers (t=3.22, df=18, P=0.010). Adrenaline spillover was higher in homozygotes than non-carriers (t=2.61, df=18, P=0.045). Administration of yohimbine produced larger, more sustained increments in noradrenaline spillover, heart rate, and anxiety in homozygotes than in the other groups. CONCLUSION: In healthy people, alpha2CDel322-325 polymorphism is associated with increased sympathetic nervous and adrenomedullary hormonal activities, both during supine rest and during pharmacologically evoked catecholamine release. Polymorphisms of the alpha2C-adrenoreceptor may help explain individual differences in predisposition to a variety of disorders of catecholaminergic function, such as cardiovascular disorders, depression or anxiety disorders.