Carlos Roncero

Brain-derived neurotrophic factor and its intracellular signaling pathways in cocaine addiction.

Cocaine addiction is one of the severest health problems faced by western countries, where there is an increasing prevalence of lifelong abuse. The most challenging aspects in the treatment of cocaine addiction are craving and relapse, especially in view of the fact that, at present, there is a lack of effective pharmacological treatment for the disorder. What is required are new pharmacological approaches based on our current understanding of the neurobiological bases of drug addiction. Within the context of the behavioral and neurochemical actions of cocaine, this paper considers the contribution of brain-derived neurotrophic factor (BDNF) and its main intracellular signaling mechanisms, including mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3K), in psychostimulant addiction. Repeated cocaine administration leads to an increase in BDNF levels and enhanced activity in the intracellular pathways (PI3K and MAPK/ERK) in the reward-related brain areas, which applies especially several days following withdrawal. It has been hypothesized that these neurochemical changes contribute to the enduring synaptic plasticity that underlies sensitized responses to psychostimulants and drug-conditioned memories leading to compulsive drug use and frequent relapse after withdrawal. Nevertheless, increased BDNF levels could also have a role as a protection factor in addiction. The inhibition of the intracellular pathways, ERK and PI3K, leads to a disruption in sensitized responses and conditioned memories associated with cocaine addiction and suggests new, potential therapeutic strategies to explore in the dependence on psychostimulants.

Brain-derived neurotrophic factor serum levels in cocaine-dependent patients during early abstinence.

Preclinical studies indicate that brain-derived neurotrophic factor (BDNF) is involved in neuroplastic changes underlying enduring cocaine-seeking following withdrawal. However, little is known about temporal changes in serum BDNF levels or the involvement of BDNF in craving and abstinence in early-abstinent cocaine-dependent patients. Twenty-three cocaine-dependent individuals (aged 33.65 ± 6.85 years) completed a two-week detoxification program at an inpatient facility. Two serum samples were collected for each patient at baseline and at the end of the protocol. Serum samples were also collected for 46 healthy controls (aged 35.52 ± 9.37 years). Demographic, consumption and clinical data were recorded for all patients. Significantly lower serum BDNF levels (p<.0001) were observed for cocaine-dependent patients at baseline compared to healthy controls. Serum BDNF levels increased significantly across 12 days of early abstinence (p=.030). Baseline BDNF levels correlated with craving (p=.034). Post-detoxification BDNF levels correlated with craving (p=.018), loss of control (p<.000), abstinence measures (p=0.031), depression (p=0.036), and anxiety (p=0.036). Post-detoxification BDNF levels also had predictive value for the loss of control measure of craving. Chronic cocaine use is associated with decreased serum BDNF. A progressive increase in serum BDNF levels during early abstinence correlates with cocaine craving and abstinence symptoms and may reflect increasing BDNF levels in different brain regions. These findings suggest that serum BDNF may be a biomarker for cocaine addiction.

Risk factors for cocaine-induced psychosis in cocaine-dependent patients.

Cocaine consumption can induce transient psychotic symptoms, expressed as paranoia or hallucinations. Cocaine induced psychosis (CIP) is common but not developed in all cases. This is the first European study on the relationship between CIP, consumption pattern variables and personality disorders. We evaluated 173 cocaine-dependent patients over 18 years; mostly males, whose average age was 33.6 years (SD=7.8). Patients attending an outpatient addictions department were enrolled in the study and subsequently systematically evaluated using SCID I and SCID II interviews for comorbid disorders, a clinical interview for psychotic symptoms and EuropASI for severity of addiction. A high proportion of cocaine dependent patients reported psychotic symptoms under the influence of cocaine (53.8%), the most frequently reported being paranoid beliefs and suspiciousness (43.9%). A logistic regression analysis was performed, finding that a model consisting of amount of cocaine consumption, presence of an antisocial personality disorder and cannabis dependence history had 66.2% sensitivity 75.8% specificity predicting the presence of CIP. In our conclusions, we discuss the relevance of evaluating CIP in all cocaine dependent-patients, and particularly in those fulfilling the clinical profile derived from our results. These findings could be useful for a clinical approach to the risks of psychotic states in cocaine-dependent patients.

Association study between the dat1 , dbh and drd2 genes and cocaine dependence in a Spanish sample

Drug addiction is a complex neuropsychiatric disorder involving the environmental and genetic factors. Genetic and physiological evidences suggest that the dopaminergic system may play an important role in cocaine abuse and dependence. Several association studies have focused on dopaminergic genes. We genotyped the Int8 and 3′UTR variable number of tandem repeats of the dopamine transporter gene (DAT1/SLC6A3), the TaqIA (rs1800497) and TaqIB (rs1079597) SNP polymorphisms within the dopamine receptor D2 gene and the 19-bp insertion/deletion and c.444G>A (rs1108580) polymorphisms of the dopamine β-hydroxylase gene (DBH) in a Spanish sample of 169 patients with cocaine addiction and 169 sex-matched controls. The case–control study showed a nominal overrepresentation of the 5R/5R genotype of the Int8 variable number of tandem repeats within DAT1 in cocaine abusers (P=0.016). However, no significant associations were detected when DAT1 haplotype frequencies or polymorphisms within the other dopaminergic genes were considered. Sample size is limited and further studies should be performed in a larger cohort.

Attention deficit hyperactivity disorder in cocaine-dependent adults: A psychiatric comorbidity analysis

BACKGROUND AND OBJECTIVES Attention deficit hyperactivity disorder (ADHD) is highly prevalent among drug abusers. We studied the psychiatric comorbidity and characteristics of cocaine use in relation to the presence of ADHD among patients with cocaine dependence. METHODS A total of 200 cocaine-dependent patients attending an Outpatient Drug Clinic participated in the study. A systematic evaluation of ADHD (CAADID-II), the severity of addiction (EuropASI) and other axes I and II psychiatric disorders was made (SCID-I and SCID-II). A descriptive, bivariate, and multivariate analysis of the data was performed. RESULTS In the multivariate analysis, the identified risk factors for the development of ADHD were a history of behavioral disorder in childhood (OR: 3.04), a lifetime history of cannabis dependence in the course of life (OR: 2.68), and age at the start of treatment (OR: 1.08). The bivariate analysis showed ADHD to be associated with other factors such as male gender, age at start of cocaine use and dependence, the amount of cocaine consumed weekly, increased occupational alteration, alcohol consumption, general psychological discomfort, depressive disorder, and antisocial personality disorder. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE We conclude that ADHD is associated with increased psychiatric comorbidity and greater severity of addiction.

Restrictions for reimbursement of interferon-free direct-acting antiviral drugs for HCV infection in Europe

All-oral direct-acting antiviral drugs (DAAs) for hepatitis C virus, which have response rates of 95% or more, represent a major clinical advance. However, the high list price of DAAs has led many governments to restrict their reimbursement. We reviewed the availability of, and national criteria for, interferon-free DAA reimbursement among countries in the European Union and European Economic Area, and Switzerland. Reimbursement documentation was reviewed between Nov 18, 2016, and Aug 1, 2017. Primary outcomes were fibrosis stage, drug or alcohol use, prescriber type, and HIV co-infection restrictions. Among the 35 European countries and jurisdictions included, the most commonly reimbursed DAA was ombitasvir, paritaprevir, and ritonavir, with dasabuvir, and with or without ribavirin (33 [94%] countries and jurisdictions). 16 (46%) countries and jurisdictions required patients to have fibrosis at stage F2 or higher, 29 (83%) had no listed restrictions based on drug or alcohol use, 33 (94%) required a specialist prescriber, and 34 (97%) had no additional restrictions for people co-infected with HIV and hepatitis C virus. These findings have implications for meeting WHO targets, with evidence of some countries not following the 2016 hepatitis C virus treatment guidelines by the European Association for the Study of Liver.

Factors associated with depression and severe depression in patients with COPD

BACKGROUND Depression is very prevalent in COPD and may be associated with poor clinical outcomes. METHOD This was a multicenter, cross-sectional study aimed at evaluating the prevalence of depression and moderate to severe depression in COPD. Depressive symptoms were evaluated with the Becks Depression Inventory. The COPD assessment test (CAT) and the EuroQoL-5 dimensions (EQ-5D) questionnaires were used to evaluate health-related quality of life (HRQoL). Severity of COPD was assessed with the BODEx index and physical activity was estimated by the mean self-declared time walked per day. RESULTS A total of 836 patients were included and up to 74.6% had some degree of depression with 51.5% having moderate to severe depression. On multivariate analysis, moderate to severe depression was associated with suicidal ideation (OR, 6.12; 95% confidence interval (CI), 1.36-28.24), worse quality of life: EQ-5D (OR, 0.89; 95%CI, 0.86-0.93) and worse CAT scores (OR, 1.32; 95%CI, 1.19-1.46). When questionnaires were not included in the analysis, significant depression was associated with the Charlson comorbidity index, minutes walked per day and BODEx score. CONCLUSIONS Depression is frequent in COPD and is associated with suicidal ideation, impaired HRQoL, increase in comorbidities, a reduction in physical activity and increased severity of COPD measured by the BODEx index.

Corticotropin releasing factor and neuroplasticity in cocaine addiction.

Corticotropin releasing factor (CRF), one of the major effectors of stress, plays a major role in the natural course of drug addiction by accelerating the acquisition of psychostimulant self-administration and increasing incentive motivation for the drug itself and for drug-associated stimuli. Stress-induced CRF is also considered a predictor of relapse and is responsible for feelings of anxiety and distress during cocaine withdrawal. Despite this knowledge, the role of CRF has not been explored in the context of recent research on reward-related learning, built on the hypothesis that neuroplastic changes in the mesocorticolimbic circuitry underlie addiction. The present review explores the effects of stress on the pattern of interaction between CRF, dopamine and glutamate in distinct structures of the mesocorticolimbic circuitry, including the ventral tegmental area (VTA), amygdala, bed nucleus of stria terminalis (BNST) and the prefrontal cortex (PFC), after acute and chronic cocaine consumption as well as in early withdrawal and protracted abstinence. A better knowledge of the neurochemical and cellular mechanisms involved in these interactions would be useful to elucidate the role of CRF in cocaine-induced neuronal plasticity, which could be useful in developing new pharmacological strategies for the treatment of cocaine addiction.

Association study of 37 genes related to serotonin and dopamine neurotransmission and neurotrophic factors in cocaine dependence

Cocaine dependence is a neuropsychiatric disorder in which both environmental and genetic factors are involved. Several processes, that include reward and neuroadaptations, mediate the transition from use to dependence. In this regard, dopamine and serotonin neurotransmission systems are clearly involved in reward and other cocaine‐related effects, whereas neurotrophic factors may be responsible for neuroadaptations associated with cocaine dependence. We examined the contribution to cocaine dependence of 37 genes related to the dopaminergic and serotoninergic systems, neurotrophic factors and their receptors through a case–control association study with 319 single nucleotide polymorphisms selected according to genetic coverage criteria in 432 cocaine‐dependent patients and 482 sex‐matched unrelated controls. Single marker analyses provided evidence for association of the serotonin receptor HTR2A with cocaine dependence [rs6561333; nominal P‐value adjusted for age = 1.9e−04, odds ratio = 1.72 (1.29–2.30)]. When patients were subdivided according to the presence or absence of psychotic symptoms, we confirmed the association between cocaine dependence and HTR2A in both subgroups of patients. Our data show additional evidence for the involvement of the serotoninergic system in the genetic susceptibility to cocaine dependence.

Psychiatric comorbidities in opioid-dependent patients undergoing a replacement therapy programme in Spain: The PROTEUS study

Opioid-dependent patients show a high rate of psychiatric comorbidities. The prevalence and characteristics of patients with dual diagnosis have not been well established in Spanish opioid agonist treatment (OAT) programmes. Thus, 621 opioid-dependent patients enrolled in OAT programmes were assessed, using the EuropASI questionnaire, for psychiatric comorbidities, which were detected in 67% of patients (anxiety 53%, mood disorders 48%, sleep disorders 41%, substance-related disorders 36%). In addition, compared with patients without a dual diagnosis, patients with dual pathology were significantly older, used benzodiazepines and cannabis in significantly greater percentages, and showed significantly more frequent infectious and non-infectious comorbidities, worse overall working status, a lower proportion of drivers and higher levels of severity regarding medical, employment, alcohol, legal, family and psychological issues. Therefore, the data showed a very high prevalence of psychiatric comorbidity in opioid-dependent patients receiving OAT in Spain and several problems frequently associated with patients with dual diagnosis. Physicians treating opioid-dependent patients should be aware of these facts to correctly identify and manage patients with a dual diagnosis.