Understanding the Scientific Basis of Post-traumatic Stress Disorder (PTSD): Precision Behavioral Management Overrides Stigmatization.

Post-traumatic stress disorder (PTSD) is a severe polygenic disorder triggered by environmental factors. Many polymorphic genes, particularly the genetic determinants of hypodopaminergia (low dopamine function), associate with a predisposition to PTSD as well as substance use disorder. Support from the National Institutes of Health for neuroimaging research and molecular, genetic applied technologies has improved understanding of brain reward circuitry functions that have inspired the development of new innovative approaches to their early diagnosis and treatment of some PTSD symptomatology and addiction. This review presents psychosocial and genetic evidence that vulnerability or resilience to PTSD can theoretically be impacted by dopamine regulation. From a neuroscience perspective, dopamine is widely accepted as a major neurotransmitter. Questions about how to modulate dopamine clinically in order to treat and prevent PTSD and other types of reward deficiency disorders remain. Identification of genetic variations associated with the relevant genotype-phenotype relationships can be characterized using the Genetic Addiction Risk Score (GARS®) and psychosocial tools. Development of an advanced genetic panel is under study and will be based on a new array of genes linked to PTSD. However, for now, the recommendation is that enlistees for military duty be given the opportunity to voluntarily pre-test for risk of PTSD with GARS, before exposure to environmental triggers or upon return from deployment as part of PTSD management. Dopamine homeostasis may be achieved via customization of neuronutrient supplementation "Precision Behavioral Management" (PBM™) based on GARS test values and other pro-dopamine regulation interventions like exercise, mindfulness, biosensor tracking, and meditation.

Apolipoprotein Gene Polymorphisms (APOB, APOC111, APOE) in the Development of Coronary Heart Disease in Ethnic Groups of Kazakhstan.

BACKGROUND: Previous Analysis of polymorphism of genes associated with the development of coronary heart disease (CHD) reveals that the frequency distribution of genotypes and alleles depends on the ethnic characteristics of the populations under study. Further impetus is derived from the well -established links between alcoholism (high prevalence in Kazakhstan region) and cardiovascular disorders. OBJECTIVES: The purpose of this study was to examine a number of apolipoprotein gene polymorphisms and correlate these alleles with changes of lipid profile in CHD patients of Kazakh and Uyghur nationalities. METHODS: Four-Hundred Forty Eight (448) males of Kazakh and Uyghur nationalities residing in Kazakhstan were evaluated and genotyped. The age range of these subjects was 30-55 years which included both afflicted and controls. Specifically, 161- Kazakhs suffered from myocardial infarction compared to 112 health controls; 80- Uyghurs suffered from CHD compared to 95 health controls. Blood lipid profiles were examined in the total cohort. Genotyping was performed by polymerase chain reaction (PCR) using oligonucleotide primers identifying; ApoB; ApoC111; and APOE gene polymorphisms. RESULTS: Initial screening revealed a significant inter-ethnic difference on the frequency of alleles associated with both the ApoB and APOE genes. We found that the X1 ApoB gene polymorphism is overrepresented in healthy Kazakhs relative to Uyghurs [86.4% in Kazakhs vs. 69.4% in Uyghurs]. Moreover, we found that the E4APOE allele was also overrepresented in healthy Kazakhs relative to Uyghurs [16.8% in Kazakhs vs. 9.5% in Uyghurs]. There was a significant relationship of polymorphisms of APOE such as ApoB and ApoC 111 with the value of lipid indices in Kazakhs. Additionally, we found that the E4 allele of the APOE gene also correlated with the value of lipid indices in Kazakhs. Further evaluation showed that the X2 allele of the ApoB and the S2 allele of the ApoCIII gene significantly associated with the lipid indices of Uyghurs. CONCLUSION: This systematic investigation confirms the association of various alleles of Apolipoprotein gene polymorphisms and contribution to aberrant lipid metabolism. Putatively at least in our population we are proposing that certain gene polymorphisms of Apolipoprotein genes such as ApoB; ApoC111; APOE ; X2 of ApoB; and S2 of ApoCIII differentially represented in either Kazakhs or Uyghurs are genetic markers of hypertriglyceridemia.

Have We Hatched the Addiction Egg: Reward Deficiency Syndrome Solution System™

This article co-authored by a number of scientists, ASAM physicians, clinicians, treatment center owners, geneticists, neurobiologists, psychologists, social workers, criminologists, nurses, nutritionist, and students, is dedicated to all the people who have lost loved ones in substance-abuse and "reward deficiency syndrome" related tragedies. Why are we failing at reducing the incidence of 'Bad Behaviors'? Are we aiming at the wrong treatment targets for behavioral disorders? We are proposing a paradigm shift and calling it "Reward Deficiency Solution System" providing evidence for its adoption.

Pharmacotherapies for Overeating and Obesity.

Obesity has become pandemic, and the annual cost in related illnesses and loss of productivity is already over $100 billion and rising. Research has shown that obesity can and does cause changes in behavior and in the brain itself that are very similar to changes caused by drugs of abuse. While food addiction is not the causal agent of all obesity, it is clear that many people no longer eat to survive, but instead survive to eat. This review considers the importance of the brain's reward system in food intake. The review also examines research developments and current treatments for obesity, including diet and exercise, psychotherapy, surgical interventions, and pharmacotherapies. Finally we discuss alterations in American society that are necessary for change to occur, and the diffculties therein.

Epigenetic Modulation of Mood Disorders.

BACKGROUND: Mood disorders are expressed in many heterogeneous forms, varying from anxiety to severe major clinical depression. The disorders are expressed in individual variety through manifestations governed by co-morbidities, symptom frequency, severity, and duration, and the effects of genes on phenotypes. The underlying etiologies of mood disorders consist of complex interactive operations of genetic and environmental factors. The notion of endophenotypes, which encompasses the markers of several underlying liabilities to the disorders, may facilitate efforts to detect and define, through staging, the genetic risks inherent to the extreme complexity of disease state. AIMS: This review evaluates the role of genetic biomarkers in assisting clinical diagnosis, identification of risk factors, and treatment of mood disorders. METHODS: Through a systematic assessment of studies investigating the epigenetic basis for mood disorders, the present review examines the interaction of genes and environment underlying the pathophysiology of these disorders. RESULTS: The majority of research findings suggest that the notion of endophenotypes, which encompasses the markers of several underlying liabilities to the disorders, may facilitate efforts to detect and define, through staging, the genetic risks inherent to the extreme complexity of the disease states. Several strategies under development and refinement show the propensity for derivation of essential elements in the etiopathogenesis of the disorders affecting drug-efficacy, drug metabolism, and drug adverse effects, e.g., with regard to selective serotonin reuptake inhibitors. These include: transporter gene expression and genes encoding receptor systems, hypothalamic-pituitary-adrenal axis factors, neurotrophic factors, and inflammatory factors affecting neuroimmune function. Nevertheless, procedural considerations of pharmacogenetics presume the parallel investment of policies and regulations to withstand eventual attempts at misuse, thereby ensuring patient integrity. CONCLUSIONS: Identification of genetic biomarkers facilitates choice of treatment, prediction of response, and prognosis of outcome over a wide spectrum of symptoms associated with affective states, thereby optimizing clinical practice procedures. Epigenetic regulation of primary brain signaling, e.g., serotonin and hypothalamic-pituitary-adrenal function, and factors governing their metabolism are necessary considerations. The participation of neurotrophic factors remains indispensable for neurogenesis, survival, and functional maintenance of brain systems.

Common Phenotype in Patients with Both Food and Substance Dependence: Case Reports.

The understanding that genes play a significant role in reward dependence and associated behavioral and drug addictions is highlighted in the emergence of Reward Deficiency Syndrome (RDS). Here we show two case reports that unequivocally indicate the definite commonality between food and drug addiction. These human cases not atypically raise the question as to how to treat these two seemingly diverse addictions. We suggest that research directed in an attempt to induce natural activation of dopaminergic reward circuitry as a form of common therapy may indeed be parsimonious.

Dopamine Genetics and Function in Food and Substance Abuse.

Having entered the genomics era with confidence in the future of medicine, including psychiatry, identifying the role of DNA and polymorphic associations with brain reward circuitry has led to a new understanding of all addictive behaviors. It is noteworthy that this strategy may provide treatment for the millions who are the victims of "Reward Deficiency Syndrome" (RDS) a genetic disorder of brain reward circuitry. This article will focus on drugs and food being mutuality addictive, and the role of dopamine genetics and function in addictions, including the interaction of the dopamine transporter, and sodium food. We will briefly review our concept that concerns the genetic antecedents of multiple-addictions (RDS). Studies have also shown that evaluating a panel of established reward genes and polymorphisms enables the stratification of genetic risk to RDS. The panel is called the "Genetic Addiction Risk Score (GARS)", and is a tool for the diagnosis of a genetic predisposition for RDS. The use of this test, as pointed out by others, would benefit the medical community by identifying at risk individuals at a very early age. We encourage, in depth work in both animal and human models of addiction. We encourage further exploration of the neurogenetic correlates of the commonalities between food and drug addiction and endorse forward thinking hypotheses like "The Salted Food Addiction Hypothesis".

Low and Normal IGF-1 Levels in Patients with Chronic Medical Disorders (CMD) is Independent of Anterior Pituitary Hormone Deficiencies: Implications for Treating IGF-1 Abnormal Deficiencies with CMD.

Over time, based on evidence-based medicine, a number of hormonal test levels including IGF-1 had been raised or lowered to meet new criteria standards. In particular, IGF-1 plasma levels have been shown in several studies to be an independent diagnostic tool in Adult Growth Hormone Deficiency (AGHD). Many endocrinology studies link low IGF-1 plasma levels with low levels of other anterior pituitary hormones (i.e., LH, FSH, and TSH). Low IGF-1 is considered by most to be between 84-100 µ/l and numerous studies recommend that raising IGF-1 to high normal range reverses Chronic Medical Diseases (CMD), improves bone mineral density (BMD), and fibromyalgia. Moreover, some studies suggest that low levels of IGF-1 by itself independent of anterior pituitary deficiencies is sufficient to determine AGHD in humans. In order to determine the relationship of low IGF-1 with that of LH, FSH, and TSH levels in subjects with CMD, we evaluated these levels (± SD) in 944 patients. Patients with IGF-1 below 84 µ/l, 100 µ/l, and 150 µ/l were accessed. 9.22% had less than 84 µ/l (SD ± 12.52); 19.9% had less than 100 µ/l (SD ± 9.54); and 51.6 had less than 150 µ/l (SD ± 26.0). Specifically, the percentages found for low LH, FSH, and TSH were only 4.2%, 4.8%, and 6.5%. We conclude that IGF-1 deficiencies occur independent of comorbid deficiencies of LH, FSH, and TSH. Finally, we propose that based on the present investigation, IGF-1 low levels between the range of 84-100 µ/l may be too low to be considered as an independent diagnostic marker to treat AGHD with CMD.

Neurogenetic Impairments of Brain Reward Circuitry Links to Reward Deficiency Syndrome (RDS): Potential Nutrigenomic Induced Dopaminergic Activation.

Work from our laboratory in both in-patient and outpatient facilities utilizing the Comprehensive Analysis of Reported Drugs (CARD)(™) found a significant lack of compliance to prescribed treatment medications and a lack of abstinence from drugs of abuse during active recovery. This unpublished, ongoing research provides an impetus to develop accurate genetic diagnosis and holistic approaches that will safely activate brain reward circuitry in the mesolimbic dopamine system. This editorial focuses on the neurogenetics of brain reward systems with particular reference to genes related to dopaminergic function. The terminology "Reward Deficiency Syndrome" (RDS), used to describe behaviors found to have an association with gene-based hypodopaminergic function, is a useful concept to help expand our understanding of Substance Use Disorder (SUD), process addictions, and other obsessive, compulsive and impulsive behaviors. This editorial covers the neurological basis of pleasure and the role of natural and unnatural reward in motivating and reinforcing behaviors. Additionally, it briefly describes the concept of natural dopamine D2 receptor agonist therapy coupled with genetic testing of a panel of reward genes, the Genetic Addiction Risk Score (GARS). It serves as a spring-board for this combination of novel approaches to the prevention and treatment of RDS that was developed from fundamental genomic research. We encourage further required studies.

Bioequivalence study of two fluoxetine capsule formulations in healthy Middle Eastern volunteers.

OBJECTIVE: To assess the bioequivalence of two fluoxetine hydrochloride capsule (20 mg) formulations (Fluoxicare capsule from Pharmacare Ltd., Chemicals and Cosmetics, Ramallah, Palestine, as test formulation, and Prozac from Eli Lilly Ltd., Basingstoke, UK, as reference formulation). DESIGN AND METHODS: The study was conducted open with a randomized 2-period crossover design and a 6-week washout period. Participants were 24 healthy male volunteers aged 18-28 years, divided into 2 groups of 12 subjects. One group was given the originator drug (reference formulation), and the other was given the test formulation. Blood samples were obtained at baseline and at 14 time points during the interval 0-96 hours after drug administration. The concentrations of the samples were assayed spectrophotometrically at 220 nm using a Shimadzu 160 A UV-visible spectrometer. We calculated the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), and time of maximum plasma concentration (tmax) for each subject. Logarithmic transformation of the AUC and Cmax was used for the statistical analyses and to assess the bioavailability of the two formulations, using analyses of variance (ANOVA) and Satherwait t-tests for unequal variances. The ANOVA performed of tmax in Cmax, and in AUC provided the appropriate intra-subject variance estimates to evaluate the 90% confidence intervals for the differences between study variables after administration of the test and reference formulations. Statistical analyses were conducted on AUC 0-4 as the extrapolated part of the AUC, a truncated area approach was adapted. RESULTS: The mean pharmacokinetic parameters for both of the drugs under study were as follows: Cmax = 61.24 (+/- 12.96) ng/ml for the test formulation, and for the reference formulation Cmax = 61.39 (+/- 14.1) ng/ml, the effects were statistically equivalent. The tmax for the test formulation was 8.25 (+/- 1.7) and 7.33 (+/- 0.96) for the reference formulation. The area under the curve to infinity (AUC 0-infinity (ng, day/ml)) for the test formulation and for the reference formulation were 293.02 (+/- 52.69) and 296.15 (+/- 61.69), respectively. CONCLUSIONS: The two formulations had equivalent pharmacokinetic parameters, were well-tolerated, and their relative bioavailability was 98.94%.

Measures of prefrontal system dysfunction in posttraumatic stress disorder.

Clinical observations have suggested that individuals who have suffered traumatic stressful events exhibit disruption in abilities mediated by frontal brain systems. Therefore, this study employed tasks sensitive to frontal lobe dysfunction, including delayed response (DR), delayed alternation (DA), object alternation (OA), delayed matching-to-sample (DMTS), and delayed nonmatching-to-sample (DNMTS), with participants having posttraumatic stress disorder (PTSD). Compared to controls, the PTSD participants were unimpaired on DA and DMTS, but they showed deficits on DR, OA, and DNMTS tasks. This pattern of results suggests disruption of functioning in selective prefrontal brain systems. Results are discussed in the context of the neuropsychological features of PTSD, as well as possible neuropathological and etiological underpinnings of this disorder.

Selective attentional processing and the right hemisphere: effects of aging and alcoholism.

Thirty-seven nonalcoholic individuals (22 women, 15 men), ages 26-76, and 36 abstinent alcoholic individuals (11 women, 25 men), ages 31-74, participated in a cued-detection task that assessed right hemisphere (RH) functioning associated with aging and alcoholism. Young controls were less reliant on cues following RH activation, which is consistent with the view that the RH has an advantage because it has the ability to attend to a broader spatial array than does the left hemisphere (LH). This RH advantage was not obtained in older controls or alcoholic participants. The pattern of results for the older nonalcoholic participants indicated that they neither benefited from valid cues following LH activation nor exhibited enhanced processing on invalid cue trials following RH activation. The results for the alcoholic participants were consistent with RH functional decline, but did not support the view that alcoholism and aging have synergistic effects.

Hypoperfusion of inferior frontal brain regions in abstinent alcoholics: a pilot SPECT study.

OBJECTIVE: This pilot study evaluated hypotheses concerning the relationship between cerebral hypoperfusion and residual deficits in the functioning of frontal brain systems in abstinent long-term alcoholics. METHOD: The participants (N = 22) were 10 healthy, abstinent alcoholics (9 men) and 12 age-equivalent nonalcoholic controls (10 men). Cerebral blood flow was observed through the use of regionally specific computer-derived quantitative analysis of single photon emission computed tomography (SPECT) perfusion images. Measures of alcohol use, abstinence and neuropsychological functioning were also obtained to relate to SPECT findings. RESULTS: A positive relationship was observed between perfusion levels in the left inferior frontal brain region and years of sobriety. Alcoholics with less than 4 years of sobriety had significantly reduced left inferior frontal perfusion compared with both nonalcoholic controls and alcoholics having longer periods of sobriety. CONCLUSIONS: The findings support the hypothesis that frontal brain abnormalities in alcoholics may subside with extended abstinence.

Comparing visual perception on conventional cabinet tachistoscopes and computer monitor tachistoscopes.

Computer monitor-based tachistoscopes (using a cathode ray tube, CRT) and conventional tachistoscopes differ in experimental control over stimulus continuity, duration, and timing accuracy. This study evaluated the perception of visual stimuli presented with the two different types of devices. An experiment was conducted to compare recognition of visuospatial stimuli (random shapes) presented laterally and centrally in the visual fields for short exposure durations (14, 29, and 43 msec), first with one device and then with another. Results indicated that the subjects' error rates and laterality patterns were similar on both types of tachistoscopes. It was concluded that perception of visual stimuli presented as continuous images on a conventional tachistoscope may be equivalent to perception of visual stimuli presented as pulsating images on a CRT. Further studies are needed using other types of visual materials to determine the range of visual stimuli for which both types of tachistoscopes measure equivalent perceptual processes.

Hypoperfusion of the cerebellum and aging effects on cerebral cortex blood flow in abstinent alcoholics: a SPECT study.

BACKGROUND: This study evaluated hypotheses concerning alcoholism, aging, and the relationship between cerebral hypoperfusion and residual deficits in the functioning of cerebellar and neocortical brain systems. METHODS: The participants were 10 healthy abstinent alcoholics (9 men, 1 woman) and 12 nonalcoholic controls (10 men, 2 women) ranging in age from 35 to 67 years. Cerebral blood flow was observed through the use of regionally specific computer-derived quantitative analysis of single photon emission computed tomography (SPECT) perfusion images. Cerebellar perfusion was measured and compared with cerebral cortex perfusion in age-equivalent subgroups of alcoholics and controls (under 55 years; 55 years and over). RESULTS: In abstinent alcoholics under age 55, cerebellar perfusion ratios were significantly reduced compared with the controls. In alcoholics and nonalcoholic controls 55 years old and older, this relationship was reversed, probably as a result of diminished cortical perfusion with aging in the alcoholics and of cerebellar decline in the controls. CONCLUSIONS: The findings support hypotheses that the residual effects of alcoholism include cerebellar brain abnormalities and that aging combined with long-term alcoholism leads to cerebral cortical decline.

Association learning and recognition memory in alcoholic Korsakoff patients.

Association learning and recognition memory were examined in 8 male alcoholic Korsakoff patients (mean age 58), and in the following 4 groups of 10 men: non-Korsakoff alcoholics (mean age 59), nonalcoholic controls (mean age 64), younger alcoholics (mean age 36), and nonalcoholic controls (mean age 37). The tasks were modeled after those used for testing memory functioning in nonhuman primates. Association learning, defined as the ability to distinguish rewarded from equally familiar nonrewarded visual stimuli, was impaired in Korsakoff patients. Korsakoff patients also were impaired on recognition memory-the ability to discriminate familiar from novel items. Results support the view of loss of multiple memory functions in alcoholic amnesia. An effect of aging was indicated by differences in performance levels between younger and older groups of non-Korsakoff participants, although the latter were superior to the Korsakoff patients.

Breakdown of cross-modal function in dementia.

To evaluate the possibility that specific language abnormalities in dementia are related to impaired cross-modal ability, the authors studied patients with Alzheimer's disease (which is characterized by a generalized language breakdown or aphasia) and patients with Parkinson's disease and dementia (a disorder associated more with selective deficits in naming than with aphasia). Both groups were initially equated for severity of dementia. Compared with nondemented patients with Parkinson's disease and age-equivalent healthy controls, patients with Alzheimer's disease and Parkinson's disease with dementia showed significant deficits in cross-modal ability. Moreover, the cross-modal deficits were significantly associated with object-naming ability. Results support the concept that language capacity and cross-modal functions are interrelated.

Impairments of brain and behavior: the neurological effects of alcohol.

Chronic heavy drinking and alcoholism can have serious repercussions for the functioning of the entire nervous system, particularly the brain. These effects include changes in emotions and personality as well as impaired perception, learning, and memory. Neuropathological and imaging techniques have provided evidence of physical brain abnormalities in alcoholics, such as atrophy of nerve cells and brain shrinkage. At the cellular level, alcohol appears to directly affect brain function in a variety of ways, primarily by interfering with the action of glutamate, gamma-aminobutyric acid, and other neurotransmitters. Neurological disorders also can result from vitamin deficiency and liver disease, two health problems that commonly occur with alcoholism. Other hypotheses, based on factors such as aging, gender, and genetics, have been developed to explain various alcohol-related neurological consequences. Many pharmacological treatments to improve neuropsychological functioning in alcoholics have been tested, but none has proved entirely successful. With prolonged abstinence, however, slow recovery of cognitive functioning can occur in some cases.

Visual laterality patterns for the perception of emotional words in alcoholic and aging individuals.

OBJECTIVE: This study evaluated hypotheses concerning alcohol-related cerebral dysfunction: (1) alcoholism, like normal chronological aging, has a more detrimental effect upon functions controlled by the right hemisphere of the brain than functions controlled by the left hemisphere; (2) interhemispheric transfer dysfunction is associated with alcoholism and aging; and (3) alcoholism and aging act synergistically. METHOD: The participants were 61 right-handed men: 18 young (ages 30 to 49 years) and 14 older (50 to 69 years) detoxified abstinent alcoholics and 14 young and 15 older healthy nonalcoholic controls. In a perceptual laterality paradigm, emotional and nonemotional words were presented to the left or right visual fields, followed by a visual masking stimulus. The participants were asked to judge the emotional valence of each word (positive, negative or neutral) and to respond verbally or manually (button presses). The dependent variable was the Critical Interstimulus Interval needed to escape the backward-masking effect. RESULTS: The alcoholics showed a significant right visual field advantage in both response mode conditions, whereas the controls did not. In addition, older alcoholics showed a selective impairment in processing negative words. CONCLUSIONS: The findings support the suggestion that alcoholics may have deficient right-hemisphere functioning. Since both the young and older alcoholic groups showed similar right visual field advantages, the idea of synergism between alcoholism and aging with respect to perceptual asymmetries was not supported.

Measures of prefrontal dysfunction after closed head injury.

Tasks sensitive to frontal lobe dysfunction (delayed response, delayed alternation, object alternation, and Wisconsin Card Sort) were administered to 20 patients with post-acute closed-head injury (CHI). Time since injury varied (6 to 280 months; mean, 48 months), as did length of coma (2 hr to 120 days; mean, 38 days). Compared to normal controls, CHI patients showed no deficits on delayed response tasks, but were impaired on delayed alternation, object alternation, and the Wisconsin Card Sort Test. Analyses of the performance profiles of the CHI patients suggested that they may have difficulty in establishing set (a consequence of damage to the orbitofrontal system).