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.

Insurance Companies Fighting the Peer Review Empire without any Validity: the Case for Addiction and Pain Modalities in the face of an American Drug Epidemic.

The United States are amid an opioid overdose epidemic; we are challenged to provide non-addicting/non-pharmacological alternatives to assist in pain attenuation. There are proven strategies available to manage chronic pain effectively without opioids. Utilization review providers for insurance companies often ignore medicine based scientific peer-reviewed studies that warn against the chronic use of opioid medications, as well as the lack of evidence to support long-term use of opioids for pain. This paradigm must change if we are to indeed change the drug-embracing culture in American chronic pain management. A barrier to treatment is pushback on the part of insurance companies especially as it relates to fighting against pain relief alternatives compared to classical analgesic agents. Pain specialists in the U.S., are compelled to find alternative solutions to help pain victims without promoting unwanted tolerance to analgesics and subsequent biological induction of the "addictive brain." It is noteworthy that reward center of the brain plays a crucial role in the modulation of nociception, and that adaptations in dopaminergic circuitry may affect several sensory and affective components of chronic pain syndromes. Possibly knowing a patient's genetic addiction risk score (GARS™) could eliminate guessing as it relates to becoming addicted.

Reward deficiency and anti-reward in pain chronification.

Converging lines of evidence suggest that the pathophysiology of pain is mediated to a substantial degree via allostatic neuroadaptations in reward- and stress-related brain circuits. Thus, reward deficiency (RD) represents a within-system neuroadaptation to pain-induced protracted activation of the reward circuits that leads to depletion-like hypodopaminergia, clinically manifested anhedonia, and diminished motivation for natural reinforcers. Anti-reward (AR) conversely pertains to a between-systems neuroadaptation involving over-recruitment of key limbic structures (e.g., the central and basolateral amygdala nuclei, the bed nucleus of the stria terminalis, the lateral tegmental noradrenergic nuclei of the brain stem, the hippocampus and the habenula) responsible for massive outpouring of stressogenic neurochemicals (e.g., norepinephrine, corticotropin releasing factor, vasopressin, hypocretin, and substance P) giving rise to such negative affective states as anxiety, fear and depression. We propose here the Combined Reward deficiency and Anti-reward Model (CReAM), in which biopsychosocial variables modulating brain reward, motivation and stress functions can interact in a 'downward spiral' fashion to exacerbate the intensity, chronicity and comorbidities of chronic pain syndromes (i.e., pain chronification).

Pain in an era of armed conflicts: Prevention and treatment for warfighters and civilian casualties.

Chronic pain is a common squealae of military- and terror-related injuries. While its pathophysiology has not yet been fully elucidated, it may be potentially related to premorbid neuropsychobiological status, as well as to the type of injury and to the neural alterations that it may evoke. Accordingly, optimized approaches for wounded individuals should integrate primary, secondary and tertiary prevention in the form of thorough evaluation of risk factors along with specific interventions to contravene and mitigate the ensuing chronicity. Thus, Premorbid Events phase may encompass assessments of psychological and neurobiological vulnerability factors in conjunction with fostering preparedness and resilience in both military and civilian populations at risk. Injuries per se phase calls for immediate treatment of acute pain in the field by pharmacological agents that spare and even enhance coping and adaptive capabilities. The key objective of the Post Injury Events is to prevent and/or reverse maladaptive peripheral- and central neural system's processes that mediate transformation of acute to chronic pain and to incorporate timely interventions for concomitant mental health problems including post-traumatic stress disorder and addiction We suggest that the proposed continuum of care may avert more disability and suffering than the currently employed less integrated strategies. While the requirements of the armed forces present a pressing need for this integrated continuum and a framework in which it can be most readily implemented, this approach may be also instrumental for the care of civilian casualties.

Neural correlates of adherence to extended-release naltrexone pharmacotherapy in heroin dependence.

Injectable extended-release naltrexone (XRNTX) presents an effective therapeutic strategy for opioid addiction, however its utility could be hampered by poor adherence. To gain a better insight into this phenomenon, we utilized blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) in conjunction with a validated cue-induced craving procedure to examine neural correlates of XRNTX adherence. We operationalized treatment adherence as the number of monthly XRNTX injections (range: 0-3) administered to a group of fully detoxified heroin-dependent subjects (n=32). Additional outcomes included urine toxicology screening and self-reported tobacco use. The presented heroin-related visual cues reliably elicited heroin craving in all tested subjects. Nine, five, three and 15 of the participants, respectively, received zero, one, two and three XRNTX injections, predicted by the individual baseline fMRI signal change in response to the cues in the medial prefrontal cortex, a brain region involved in inhibitory self-control and emotional appraisal. The incidence of opioid-positive urines during the XRNTX therapy was low and remained about half the pre-treatment rate after the XRNTX ended. During the treatment, cigarette smoking behaviors followed patterns of opioid use, while cocaine consumption was increased with reductions in opioid use. The present data support the hypothesis that medial prefrontal cortex functions are involved in adherence to opioid antagonist therapy. A potential role of concurrent non-opioid addictive substances consumption during the XRNTX pharmacotherapy warrants further investigation. Our findings set the stage for further bio-behavioral investigations of the mechanisms of relapse prevention in opioid dependence.

Effects of acute cortisol and cocaine administration on attention, recall and recognition task performance in individuals with cocaine dependence.

This study investigated the effects of acute cocaine administration on cognition, and whether these can be modeled using exogenous hydrocortisone, because cocaine-induced cortisol elevations may influence its cognitive effects. Twelve cocaine-dependent individuals received an intravenous bolus of cortisol (0.5 or 0.2 mg/kg) and cocaine (0.2 mg/kg) in a double-blind randomized placebo-controlled and counterbalanced fashion. Cognitive testing included verbal tasks of vigilance attention, free recall and recognition memory before the boluses and at 20, 60 and 100 min thereafter. The statistical analysis investigated dose response effects while accounting for all sources of variance in the design. No effects of low dose cocaine were found on any variables. Low dose cortisol enhanced and high dose impaired vigilance attention, and a trend was found for the same dose response profile on twice-heard words. An opposite trend, inconsistent with prior research on cortisol and cognition, was observed for recognition: low dose impaired and high dose enhanced recognition of once-heard words, and a very weak trend was found for recognition of new words. These findings, though tempered by design limitations, suggest a complex non-linear cortisol attention/recognition dose-response relationship and call for further research to elucidate cortisol's effects on cognition and their role in the pathophysiology of cocaine dependence.

Gender differences in cocaine craving among non-treatment-seeking individuals with cocaine dependence.

The purpose of this pilot study was to evaluate potential gender differences in cocaine craving among non-treatment seekers with cocaine dependence. We examined 10 female and 11 male individuals matched by demographic characteristics and severity of drug use; we used a multidimensional questionnaire that assesses various aspects of craving: (a) current intensity, (b) projected intensity, (c) resistance to use cocaine, (d) responsiveness to drug-related conditioned stimuli, and (e) imagined likelihood of use if in a setting with access to drugs. Other instruments utilized were the Hamilton Rating Scale for Depression and Addiction Severity Index. Female subjects had higher total craving scores (p < .05), with post hoc tests showing more present desire to use cocaine and responsivity to drug-conditioned stimuli, along with lower scores on the desire not to use cocaine. In exploratory analyses, we found greater depressive symptomatology (p = .02) and severity of family/social problems (p = .02) in females than their males counterparts. These results suggest that gender may influence different aspects of cocaine craving. As estrogen is purported to modulate craving-related dopaminergic systems, further studies will be needed to confirm these observed gender differences and to investigate their possible mechanisms, particularly estrogen-dopamine interactions and their effect on craving and mood.

Inverse relationship between plasma epinephrine and testosterone levels during acute glucoprivation in healthy men.

In healthy men, a decrease in plasma testosterone levels was observed in the context of metabolic stress. While physiological mechanisms underlying this response are unclear, there are several lines of evidence suggesting circulating epinephrine's influence on plasma testosterone levels. The purpose of this study was to directly relate stress-induced changes in plasma testosterone and epinephrine. The stressor used was blockade of glucose metabolism with pharmacological doses (40 mg/kg) of 2 deoxyglucose (2DG). Arterial plasma samples from 10 healthy males were assayed at 20 minutes intervals for 60 minutes for the concentrations of testosterone, epinephrine and related biochemicals. Bolus administration of 2DG resulted in progressive decline in testosterone and increases in epinephrine and norepinephrine plasma levels (mean change from baseline: 29, 2530 and 186%, respectively). Inverse correlation was detected between both absolute (r(s)=-0.72; df=8; p=0.017) and baseline-corrected testosterone concentrations at the 60 minute time point and epinephrine area under the curve values. Our results suggest that adrenomedullary activation may be involved in stress-induced testosterone effects. The implications of these data for the understanding of the role of catecholamines in glucoprivic stress response are discussed.

Clinical outcomes following cocaine infusion in nontreatment-seeking individuals with cocaine dependence.

BACKGROUND: In this study we explored if laboratory-based cocaine administration to human subjects was associated with long-term adverse outcomes. METHODS: Twenty-one non--reatment seeking individuals with cocaine dependence were evaluated at baseline and again 5 and 10 months following cocaine infusion in a brain imaging study. Outcomes included computer-driven multidimensional clinical assessments and radioimmunoassay of hair. For comparison, identical data were collected from 19 cocaine-dependent subjects who did not receive the infusion. RESULTS: The infused and noninfused groups did not differ on frequency of cocaine use (corroborated by radioimmunoassay of hair), Addiction Severity Index drug composite score, or Hamilton Rating Scale for Depression score at both follow-up time points. In a time-related trend analysis, both groups showed significant reductions in frequency of cocaine use. CONCLUSIONS: Laboratory-based cocaine administration can be a safe paradigm even in individuals who are not engaged in treatment.

Ultrarapid opioid detoxification: effects on cardiopulmonary physiology, stress hormones and clinical outcomes.

This study explored the acute and long-term consequences of ultrarapid opioid detoxification (URD) in individuals with opioid dependence. In an open case series, seven patients underwent URD and subsequent treatment with daily naltrexone. Structured interviews, integrated rehabilitation and hair sampling were employed in the 12-week course of longitudinal follow-up. Cardiac and pulmonary physiology did not change significantly during the anesthesia phase of URD, but plasma ACTH and cortisol levels increased 15- and 13-fold, respectively. Marked withdrawal and tachypnea in all patients and respiratory distress in one patient occurred during the acute post-anesthesia phase. Withdrawal scores were significantly elevated for 3 weeks compared with baseline in the face of minimal self-reported craving for opioids. Anxiety, depression and vegetative symptoms improved gradually. Four patients remained abstinent of opioid use, two reported a brief period of opioid intake and one relapsed into daily opioid consumption. Given its effect on breathing and stress hormones, this procedure should be conducted by experienced anesthesiologists. The fact that URD and subsequent naltrexone treatment appears to cause a dissociation effect in the usual relationship between withdrawal and craving has implications for behavioral pharmacology. Further research is needed on the efficacy, safety, mechanisms and neurobiological sequelae of the procedure.

The validity of self-reported drug use in non-treatment seeking individuals with cocaine dependence: correlation with biochemical assays.

Accurate estimate of drug exposure plays an important role in studies of the neurobiology of drug dependence. The validity of self-reported drug use by subjects participating in such studies has not been well established. This study examined the relationship between self-reported drug use and biological markers in 18 non-treatment-seeking cocaine-dependent individuals participating in research on the effects of cocaine on the brain. A significant relationship was found between self-reported frequency of cocaine use and hair cocaine concentration. Frequency of alcohol use correlated significantly with plasma carbohydrate-deficient transferrin and aspartate aminotransferase levels. These results suggest that self-reported substance use in non-treatment seeking research subjects is generally valid.

Effects of acute metabolic stress on striatal dopamine release in healthy volunteers.

Several lines of evidence indicate that a variety of metabolic stressors, including acute glucose deprivation are associated with dopamine release. Pharmacologic doses of the glucose analogue, 2-deoxyglucose (2DG) cause acute glucoprivation and are associated with enhanced dopamine turnover in preclinical studies. In this study, we utilized [11C]raclopride PET to examine 2DG-induced striatal dopamine release in healthy volunteers. Six healthy volunteers underwent PET scans involving assessment of 2DG-induced (40 mg/kg) decrements in striatal binding of the D(2)/D(3) receptor radioligand [11C]raclopride. Decreases in [11C]raclopride specific binding reflect 2DG-induced changes in synaptic dopamine. Specific binding significantly decreased following 2DG administration, reflecting enhanced synaptic dopamine concentrations (p =.02). The administration of 2DG is associated with significant striatal dopamine release in healthy volunteers. Implications of these data for investigations of the role of stress in psychiatric disorders are discussed.

Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia.

OBJECTIVE: This study sought to determine whether thought disorder induced in healthy volunteers by the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine resembles the thought disorder found in patients with schizophrenia. METHOD: The Scale for the Assessment of Thought, Language, and Communication was used to assess thought disorder in healthy volunteers (N = 10) who received subanesthetic doses of ketamine and in a group of clinically stable inpatients with schizophrenia (N = 15) who did not receive ketamine. RESULTS: Mean scores on the Scale for the Assessment of Thought, Language, and Communication for patients with schizophrenia and healthy volunteers receiving ketamine did not differ significantly. Moreover, three of the four highest rated test items in both groups were the same. CONCLUSIONS: These data suggest that ketamine-induced thought disorder in healthy volunteers is not dissimilar to the thought disorder in patients with schizophrenia and provide support for the involvement of the NMDA receptor in a cardinal symptom of schizophrenia.

Depressive symptomatology and cocaine-induced pituitary-adrenal axis activation in individuals with cocaine dependence.

The hypothalamic-pituitary-adrenal (HPA) axis plays a role in cocaine dependence and major depressive disorder. The authors examined the correlation between baseline depressive symptomatology and pituitary-adrenal axis activation induced by acute cocaine challenge. Twelve patients with cocaine dependence were administered an iv bolus of cocaine (0.6 mg/kg) and their plasma was assayed for levels of adrenocorticotropic hormone (ACTH) and cortisol. Depressive symptomatology was assessed with total Hamilton rating scale for depression (HRSD) scores and its vegetative and cognitive superfactors. Cocaine produced a mean increase from baseline of 261% for ACTH and 73% for cortisol plasma levels. Changes in ACTH (r=0.69) and cortisol (r=0.59) were positively and significantly correlated with total HRSD scores and its vegetative, but not cognitive, factor symptom cluster. These results suggest that the HPA axis may be involved in affective disturbances associated with the use of cocaine. Implications of these data for the pathophysiology of cocaine dependence are discussed.

Effects of atypical antipsychotic drug treatment on amphetamine-induced striatal dopamine release in patients with psychotic disorders.

Clozapine, risperidone, and other new "atypical" antipsychotic agents are distinguished from traditional neuroleptic drugs by having clinical efficacy with either no or low levels of extrapyramidal symptoms (EPS). Preclinical models have focused on striatal dopamine systems to account for their atypical profile. In this study, we examined the effects of clozapine and risperidone on amphetamine-induced striatal dopamine release in patients with psychotic disorders. A novel 11C-raclopride/PET paradigm was used to derive estimates of amphetamine-induced changes in striatal synaptic dopamine concentrations and patients were scanned while antipsychotic drug-free and during chronic treatment with either clozapine or risperidone. We found that amphetamine produced significant reductions in striatal 11C-raclopride binding during the drug-free and antipsychotic drug treatment phases of the study which reflects enhanced dopamine release in both conditions. There were no significant differences in % 11C-raclopride changes between the two conditions indicating that these atypical agents do not effect amphetamine-related striatal dopamine release. The implications for these data for antipsychotic drug action are discussed.

Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response.

OBJECTIVE: Clozapine and risperidone were the first two "second-generation" antipsychotic drugs approved for schizophrenia. There is currently little information about their comparative efficacy from head-to-head clinical trials. The purpose of this study was to examine the comparative efficacy of clozapine and risperidone for positive and negative symptoms, depression, parkinsonian side effects, and indexes of neuroendocrine function in schizophrenic patients who met a priori criteria for partial response to traditional neuroleptic agents. METHOD: After a baseline fluphenazine treatment period, 29 patients participated in a 6-week, double-blind, parallel-group comparison of the effects of these agents. RESULTS: Clozapine was superior to risperidone for positive symptoms and parkinsonian side effects, but there were no significant differences between the drugs on two measures of negative symptoms, Brief Psychiatric Rating Scale total scores, and depression scores. The clozapine patients, but not the risperidone patients, demonstrated significant reductions from the fluphenazine baseline in positive symptoms, total symptoms, and depression. In addition, clozapine produced fewer effects on plasma prolactin than risperidone or fluphenazine. The mean daily doses during week 6 of the trial were 403.6 mg of clozapine and 5.9 mg of risperidone. CONCLUSIONS: The findings from this study indicate that these drugs have both important differences and similarities in their comparative efficacy in chronically ill, partially responsive patients with schizophrenia. Further research on second-generation antipsychotic drugs in this patient population that addresses key methodological issues, such as optimal dose and treatment duration, are needed.

The effects of pharmacological doses of 2-deoxyglucose on cerebral blood flow in healthy volunteers.

The effects of glucose deprivation on cerebral blood flow (CBF) have been extensively investigated during insulin-induced hypoglycemia in laboratory animals. Pharmacological doses of glucose analog, 2-deoxyglucose (2DG), is an alternative glucoprivic agent that in contrast to insulin, directly inhibits glycolysis and glucose utilization. Both glucoprivic conditions markedly increase CBF in laboratory animals. How 2DG affects CBF in humans is still undetermined. In the present study we have employed H215O positron emission tomography (PET) to examine the effects of pharmacological doses of 2DG (40 mg/kg) on regional and global cerebral blood flow in 10 brain areas in 13 healthy volunteers. 2DG administration significantly raised regional CBF (rCBF) in the cingulate gyrus, sensorimotor cortex, superior temporal cortex, occipital cortex, basal ganglia, limbic system and hypothalamus. 2DG produced a trend towards elevated CBF in whole brain and frontal cortex, while no changes were observed in the corpus callosum and thalamus. In addition, 2DG significantly decreased body temperature and mean arterial pressure (MAP). Maximal percent changes in hypothalamic rCBF were significantly correlated with maximal changes in body temperature but not with MAP. These results indicate that cerebral glucoprivation produced by pharmacological doses of 2DG is accompanied by widespread activation of cortical and subcortical blood flow and that the blood flow changes in the hypothalamus may be related to 2DG-induced hypothermia.

Mechanism of peripheral noradrenergic stimulation by clozapine.

Elevated plasma norepinephrine (NE) levels is a relatively consistent clinical effect of clozapine. Plasma NE levels reflect an interplay of release, reuptake, metabolism, and excretion. To explore the mechanism of clozapine-induced plasma NE elevation, we measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE (3H-NE) in schizophrenic patients treated with clozapine, fluphenazine, or placebo. Clozapine-treated patients had markedly higher levels of NE than did the patients treated with fluphenazine or placebo. NE spillover averaged more than three times higher in clozapine-treated patients; whereas NE clearance did not differ among the groups. Production of 3H-dihydroxyphenylglycol (3H-DHPG), a purely intraneuronal metabolite of 3H-NE in clozapine-treated patients was normal, indicating that clozapine did not affect neuronal uptake of NE. Because plasma levels of DHPG and dihydroxyphenylacetic acid (DOPAC), deaminated metabolites of catecholamines, in clozapine-treated patients were normal, clozapine also did not seem to inhibit intraneuronal monoamine oxidase (MAO). High plasma NE levels in clozapine-treated patients, therefore, resulted from increased NE spillover rather than decreased reuptake, metabolism, or clearance.

Dopamine D2 receptor density and personal detachment in healthy subjects.

OBJECTIVE: The purpose of this study was to examine the relationship between the personality trait involving personal detachment and dopamine D2 receptor specific binding in healthy subjects. METHOD: Eighteen adult subjects completed the Karolinska Scales of Personality and the Tridimensional Personality Questionnaire and participated in a study that used [11C]raclopride positron emission tomography (PET) to quantify striatal D2 receptor binding. RESULTS: A significant relationship was found between D2 receptor specific binding and detachment scores on the Karolinska Scales of Personality but not between D2 receptor specific binding and attachment scores on the Tridimensional Personality Questionnaire. In an exploratory analysis, the authors found a significant relationship between binding and the sentimentality cluster on the Tridimensional Personality Questionnaire but on no other personality clusters scores on the Tridimensional Personality Questionnaire or Karolinska Scales of Personality. CONCLUSIONS: These findings replicate those of a recent report that personal detachment scores on the Karolinska Scales of Personality are related to dopamine D2 receptor density and extends this finding by suggesting that the relationship is relatively specific to the trait defined by the Karolinska Scales of Personality and does not generalize to other forms of detachment.