Cocaine-induced Psychosis and Brain-derived Neurothrophic Factor in Patients with Cocaine Dependence : Report of Two Cases

Brain-derived neurotrophic factor (BDNF) is linked to numerous brain functions. In addition, BDNF alterations contribute to neurological, mental, and addictive disorders. Cocaine dependence has received much attention recently due to its prevalence and psychological effects. Symptoms of psychosis are one of the most serious adverse events precipitated by cocaine use. It is particularly important to identify patients at risk of developing cocaine-induced psychosis (CIP). We described two cases of patients with cocaine dependence who presented with CIP and had changes in their BDNF levels during the psychotic episode. BDNF levels were initially low in both patients, and then decreased by more than 50% in association with CIP. The relationship between BDNF and psychosis is described in the literature. These cases revealed that BDNF levels decreased during a CIP episode and, thus, it is necessary to investigate BDNF and its relationship with CIP further

Inhaled Loxapine for Agitation in Intoxicated Patients : A Case Series

Episodes of agitation are frequent in intoxicated patients who have a substance use disorder, a psychiatric disorder or both (dual diagnosis). For managing the agitation, it is necessary to act promptly in a safe environment and addressing any underlying etiology. Inhaled loxapine improves symptoms of agitation in adults with psychiatric disorders (eg, schizophrenia) within 10 minutes of administration. Recently, some reports have documented the usefulness of loxapine in dual diagnoses patients with agitation. However, the efficacy of loxapine in intoxicated patients has not been deeply addressed. This report describes a case series of 12 patients (with addiction or dual disorder) who received inhaled loxapine for symptoms of psychomotor agitation during intoxication with different substances (eg, alcohol, cannabis, or cocaine) at 1 center in Spain. Data from 12 patients were reviewed, 5 patients were attended at the emergency room, 4 at the addiction and dual diagnosis unit, and 3 were treated during hospitalization for detoxification. All patients were under effects of substances. They had substance use disorder (including cannabis, cocaine, alcohol, hypnotics, and hallucinogens), and almost all (90%) presented 1 or more psychiatric disorders. One dose of inhaled loxapine was effective in 9 patients (75%), and in 3 patients, a second dose was required. Only mild dizziness was reported in 1 patient after the second dose. The acute agitation was effectively and quickly managed with inhaled loxapine in all intoxicated patients and enabled the appropriate clinical evaluation of the agitated state and the patient's management

Insomnia Symptoms in Patients With Substance Use Disorders During Detoxification and Associated Clinical Features

Background: Insomnia is highly prevalent in patients with substance use disorders (SUD), and it has been related to a worse course of addiction. Insomnia during detoxification in a hospital has not been adequately studied. This study aims to compare sociodemographic, clinical, and psychopathological characteristics of SUD patients undergoing a detoxification program, by comorbidity and insomnia symptoms. Methodology: We recruited 481 patients who received pharmacological and psychotherapeutic treatment for detoxification. They were evaluated through semi-structured interviews, standardized questionnaires, and a specific sleep log. A bivariate and multivariate analysis of the data was performed. Results: Insomnia was reported by 66.5% patients, with sleep-maintenance insomnia the most frequent issue, followed by early morning awakening and sleep-onset insomnia. Patients with alcohol use disorder and cannabis use disorder had higher prevalence of sleep-onset insomnia. Patients with cocaine and heroin use disorder had higher prevalence of sleep-maintenance insomnia. Independent factors that allowed the identification of insomnia symptoms included being female (OR: 3.43), polysubstance use (OR: 2.85), comorbid anxiety disorder (OR: 2.02), and prior admission for detoxification (OR: 1.22). Conclusions: Insomnia symptoms are very prevalent in patients admitted for detoxification. The diagnosis and therapeutic strategies for the insomnia symptoms should be improved, especially in women and in patients with greater addiction severity and with anxiety disorders

Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence

Cocaine reward and reinforcing effects are mediated mainly by dopaminergic neurotransmission. In this study, we aimed at evaluating gene expression changes induced by acute cocaine exposure on SH-SY5Y-differentiated cells, which have been widely used as a dopaminergic neuronal model. Expression changes and a concomitant increase in neuronal activity were observed after a 5 μM cocaine exposure, whereas no changes in gene expression or in neuronal activity took place at 1 μM cocaine. Changes in gene expression were identified in a total of 756 genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as mitogen-activeated protein kinase (MAPK), CREB, neurotrophin and neuregulin signaling pathways. Some genes displaying altered expression were subsequently targeted with predicted functional single-nucleotide polymorphisms (SNPs) in a case-control association study in a sample of 806 cocaine-dependent patients and 817 controls. This study highlighted associations between cocaine dependence and five SNPs predicted to alter microRNA binding at the 3′-untranslated region of the NFAT5 gene. The association of SNP rs1437134 with cocaine dependence survived the Bonferroni correction for multiple testing. A functional effect was confirmed for this variant by a luciferase reporter assay, with lower expression observed for the rs1437134G allele, which was more pronounced in the presence of hsa-miR-509. However, brain volumes in regions of relevance to addiction, as assessed with magnetic resonance imaging, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is upregulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence

Association of the PLCB1 gene with drug dependence

Genetic factors involved in the susceptibility to drug addiction still remain largely unknown. MiRNAs seem to play key roles in the drug-induced plasticity of the brain that likely drives the emergence of addiction. In this work we explored the role of miRNAs in drug addiction. With this aim, we selected 62 SNPs located in the 3'UTR of target genes that are predicted to alter the binding of miRNA molecules and performed a case-control association study in a Spanish sample of 735 cases (mainly cocaine-dependent subjects with multiple drug dependencies) and 739 controls. We found an association between rs1047383 in the PLCB1 gene and drug dependence that was replicated in an independent sample (663 cases and 667 controls). Then we selected 9 miRNAs predicted to bind the rs1047383 region, but none of them showed any effect on PLCB1 expression. We also assessed two miRNAs binding a region that contains a SNP in linkage disequilibrium with rs1047383, but although one of them, hsa-miR-582, was found to downregulate PLCB1, no differences were observed between alleles. Finally, we explored the possibility that PLCB1 expression is altered by cocaine and we observed a significant upregulation of the gene in the nucleus accumbens of cocaine abusers and in human dopaminergic-like neurons after cocaine treatment. Our results, together with previous studies, suggest that PLCB1 participates in the susceptibility to drug dependence

Factores asociados al consumo de sustancias en población mayor de 65 años y evolución y pronóstico tras la abstinencia

Durante las últimas décadas, se está produciendo un importante envejecimiento poblacional que requiere de una atención especializada. Entre la psicopatología que se experimenta entre los adultos mayores, el Trastorno por consumo de sustancias constituye un fenómeno creciente. Sin embargo, sigue infravalorado actualmente, mal identificado e infradiagnosticado y, por todo ello, tratado de forma deficiente. Se ha hipotetizado acerca de la existencia de múltiples factores relacionados tanto biológicos como psicosociales, postulándose acerca de las diferencias atribuibles al sexo del paciente. Así mismo, existe evidencia de que los ancianos con problemática de consumo tienden a presentar consecuencias negativas relacionadas de índole médico y social. Entre estos efectos negativos, destaca la afectación cognitiva relacionada con el consumo crónico de alcohol y fármacos de prescripción y la posibilidad de mejoría tras lograr la abstinencia a sustancias. Finalmente, los estudios indican que tanto la adherencia a los regímenes de tratamiento como la evolución de la patologia y el porcentaje de logro de abstinencia son más favorable entre los pacientes ancianos con problemas de consumo que en la población general. El objetivo de esta tesis doctoral, que se presenta por compendio de publicaciones, es profundizar en el conocimiento del Trastorno por consumo de sustancias en población adulta mayor de 65 años. En los dos primeros artículos centrados en cognición, el consumo de sustancias en mayores demuestra generar consecuencias perjudiciales, alterando diversos dominios cognitivos con el consumo crónico de alcohol y benzodiacepinas. Así mismo, estas alteraciones cognitivas secundarias mejoran tras lograr la abstinencia durante el proceso de tratamiento. En el tercer artículo, se estudian las características en población mayor consumidora, así como las diferencias de tipo sociodemográfico, clínico y terapéutico atribuibles al sexo del paciente y que interfieren en el tipo de abordaje que deberemos llevar a cabo. La población mayor afecta de un Trastorno por consumo de sustancias mantiene una mejor adherencia a los regímenes de tratamiento y logra en mayor porcentaje la abstinencia a sustancias que la población general, lo que indica una evolución y un pronóstico más favorables. Por tanto, la no detección o filiación del problema sería el único impedimento para lograr un resultado favorable en mayores. La implantación de programas de tratamiento especificos resultarían de utilidad para asegurar un outcome favorable y lograr retornar a estas persones a sus capacidades cognitivas propias de su edad.For the last decades we have been living a significant phenomenon of aging population that requires special attention. Among the different psychopathologies affecting this group of old adults, substance use disorder keeps increasing. However it is still undervalued, misidentified and infradiagnosed, and therefore does not receive the right treatment. There are several hypotheses around the existence of multiple factors, both biological and psychosocial, related to substance use with sex differences between men and women. There is evidence that old age patients with substance use disorder tend to suffer from negative medical and social consequences. Among these negative effects we can highlight the cognitive impairment related to alcohol and prescription drug abuse, and the recovery after achieving abstinence. Studies indicate that adherence to treatment, progress of the pathology and the percentage of success in achieving abstinence are more favorable amount elderly people compared to general population. The objective of this doctoral thesis, presented as a compendium of publications, is to deepen on the knowledge of substance among in elderly population over 65 years old. In the first two articles focused on cognition, substance use disorder among the elderly demonstrates its harmful consequences, altering several cognitive domains with alcohol and benzodiazepines chronic consumption. Likewise, this secondary cognitive impairment improves when abstinence is achieved during the treatment process. In the third article the characteristics in elderly consumption population are studied, as well as the sociodemographic, clinical and therapeutical differences associated to the sex of the patient that interfere with the type of treatment that should be used. Elderly population suffering from substance use disorder has better adherence to treatment and achieves abstinence in a higher percentage, which indicates a more favorable evolution and outcome. Therefore, an infradiagnosis will be the main barrier in order to achieve a positive result among the elderly. The implementation of tailored treatment programs would be particularly favorable in order to avoid harm and help this population to recover their own age-specific cognitive level

Factores asociados al consumo de sustancias en población mayor de 65 años y evolución y pronóstico tras la abstinencia /

Durante las últimas décadas, se está produciendo un importante envejecimiento poblacional que requiere de una atención especializada. Entre la psicopatología que se experimenta entre los adultos mayores, el Trastorno por consumo de sustancias constituye un fenómeno creciente. Sin embargo, sigue infravalorado actualmente, mal identificado e infradiagnosticado y, por todo ello, tratado de forma deficiente. Se ha hipotetizado acerca de la existencia de múltiples factores relacionados tanto biológicos como psicosociales, postulándose acerca de las diferencias atribuibles al sexo del paciente. Así mismo, existe evidencia de que los ancianos con problemática de consumo tienden a presentar consecuencias negativas relacionadas de índole médico y social. Entre estos efectos negativos, destaca la afectación cognitiva relacionada con el consumo crónico de alcohol y fármacos de prescripción y la posibilidad de mejoría tras lograr la abstinencia a sustancias. Finalmente, los estudios indican que tanto la adherencia a los regímenes de tratamiento como la evolución de la patologia y el porcentaje de logro de abstinencia son más favorable entre los pacientes ancianos con problemas de consumo que en la población general. El objetivo de esta tesis doctoral, que se presenta por compendio de publicaciones, es profundizar en el conocimiento del Trastorno por consumo de sustancias en población adulta mayor de 65 años. En los dos primeros artículos centrados en cognición, el consumo de sustancias en mayores demuestra generar consecuencias perjudiciales, alterando diversos dominios cognitivos con el consumo crónico de alcohol y benzodiacepinas. Así mismo, estas alteraciones cognitivas secundarias mejoran tras lograr la abstinencia durante el proceso de tratamiento. En el tercer artículo, se estudian las características en población mayor consumidora, así como las diferencias de tipo sociodemográfico, clínico y terapéutico atribuibles al sexo del paciente y que interfieren en el tipo de abordaje que deberemos llevar a cabo. La población mayor afecta de un Trastorno por consumo de sustancias mantiene una mejor adherencia a los regímenes de tratamiento y logra en mayor porcentaje la abstinencia a sustancias que la población general, lo que indica una evolución y un pronóstico más favorables. Por tanto, la no detección o filiación del problema sería el único impedimento para lograr un resultado favorable en mayores. La implantación de programas de tratamiento especificos resultarían de utilidad para asegurar un outcome favorable y lograr retornar a estas persones a sus capacidades cognitivas propias de su edad.For the last decades we have been living a significant phenomenon of aging population that requires special attention. Among the different psychopathologies affecting this group of old adults, substance use disorder keeps increasing. However it is still undervalued, misidentified and infradiagnosed, and therefore does not receive the right treatment. There are several hypotheses around the existence of multiple factors, both biological and psychosocial, related to substance use with sex differences between men and women. There is evidence that old age patients with substance use disorder tend to suffer from negative medical and social consequences. Among these negative effects we can highlight the cognitive impairment related to alcohol and prescription drug abuse, and the recovery after achieving abstinence. Studies indicate that adherence to treatment, progress of the pathology and the percentage of success in achieving abstinence are more favorable amount elderly people compared to general population. The objective of this doctoral thesis, presented as a compendium of publications, is to deepen on the knowledge of substance among in elderly population over 65 years old. In the first two articles focused on cognition, substance use disorder among the elderly demonstrates its harmful consequences, altering several cognitive domains with alcohol and benzodiazepines chronic consumption. Likewise, this secondary cognitive impairment improves when abstinence is achieved during the treatment process. In the third article the characteristics in elderly consumption population are studied, as well as the sociodemographic, clinical and therapeutical differences associated to the sex of the patient that interfere with the type of treatment that should be used. Elderly population suffering from substance use disorder has better adherence to treatment and achieves abstinence in a higher percentage, which indicates a more favorable evolution and outcome. Therefore, an infradiagnosis will be the main barrier in order to achieve a positive result among the elderly. The implementation of tailored treatment programs would be particularly favorable in order to avoid harm and help this population to recover their own age-specific cognitive level

Mood disorders and severity of addiction in alcohol-dependent patients could be mediated by sex differences

Background: Alcohol dependence is highly prevalent in the general population; some differences in alcohol use and dependence between women and men have been described, including outcomes and ranging from biological to social variables. This study aims to compare the severity of alcohol dependence with clinical and psychopathological characteristics between sexes. Methods: A cross-sectional descriptive study was conducted in alcohol-dependent outpatients; the recruitment period was 7 years. The assessment of these patients was carried out by obtaining sociodemographic characteristics and using the Semi-structured Clinical Interview for Axis I and II (SCID-I and SCID-II), European version of the Addiction Severity Index (EuropASI), Beck Depression Inventory (BDI), and State-Trait Anxiety Inventory (STAI) scales. Variables were compared and analyzed. Results: The sample was composed of 178 patients (74.2% males and 25.8% females) with a mean age of 46.52 ± 9.86. No sociodemographic differences were found between men and women. Females had a higher rate of suicide attempts and depression symptoms at the treatment onset. When results of EuropASI were compared, females had worse psychological and employment results than males. According to consumption variables, males had an earlier onset of alcohol use, had more regular alcohol use, and develop alcohol dependence earlier than females. Conclusions: According to results, there are sex-dependent differences (severity and other variables such as mood or suicide) in alcohol dependence. Thus, this may implicate the need of future specific research and treatment programs based on the specific necessities of each sex

Psychotic Symptoms Associated with the use of Dopaminergic Drugs, in Patients with Cocaine Dependence or Abuse.

In the field of dual diagnosis, physicians are frequently presented with pharmacological questions. Questions about the risk of developing psychotic symptoms in cocaine users who need treatment with dopaminergic drugs could lead to an undertreatment. Review the presence of psychotic symptoms in patients with cocaine abuse/dependence, in treatment with dopaminergic drugs. Systematic PubMed searches were conducted including December 2014, using the keywords: "cocaine", dopaminergic drug ("disulfuram-methylphenidate-bupropion-bromocriptine-sibutramineapomorphine- caffeine") and ("psychosis-psychotic symptoms-delusional-paranoia"). Articles in English, Spanish, Portuguese, French, and Italian were included. Articles in which there was no history of cocaine abuse/dependence, absence of psychotic symptoms, systematic reviews, and animal studies, were excluded. 313 papers were reviewed. 7 articles fulfilled the inclusion-exclusion criteria. There is a clinical trial including 8 cocaine-dependent patients using disulfiram in which 3 of them presented psychotic symptoms and 6 case-reports: disulfuram (1), methylphenidate (1), disulfiram with methylphenidate (2), and bupropion (2), reporting psychotic symptoms, especially delusions of reference and persecutory ideation. Few cases have been described, which suggests that the appearance of these symptoms is infrequent. The synergy of dopaminergic effects or the dopaminergic sensitization in chronic consumption are the explanatory theories proposed by the authors. In these cases, a relationship was found between taking these drugs and the appearance of psychotic symptoms. Given the low number of studies found, further research is required. The risk of psychotic symptoms seems to be acceptable if we compare it with the benefits for the patients but a closer monitoring seems to be advisable

Neuroticism associated with cocaine-induced psychosis in cocaine-dependent patients: a cross-sectional observational study.

BACKGROUND:Cocaine consumption can induce transient psychotic symptoms, which has been correlated with more severe addiction and aggressive behavior. However, little is known about the nature of the relationship between personality traits and psychotic symptoms in cocaine-dependent patients. This study examined the relationship between neuroticism and cocaine-induced psychosis. METHODS:A total of 231 cocaine-dependent patients seeking treatment were recruited to the study. Personality was evaluated by the Zuckerman-Kuhlman Personality Questionnaire. Cocaine-induced psychosis questionnaire, SCID-I, and SCID-II were used to evaluate comorbidity and clinical characteristics. Data analysis was performed in three steps: descriptive, bivariate, and multivariate analyses. RESULTS:Cocaine-induced psychosis was reported in 65.4% of the patients and some personality disorder in 46.8%. Two personality dimensions (Neuroticism-Anxiety and Aggression-Hostility) presented a significant effect on the risk of experiencing psychotic symptoms (t(229) = 2.69, p = 0.008; t(229) = 2.06, p = 0.004), and patients with psychotic symptoms showed higher scores in both variables. On the multivariate analysis, only Neuroticism remained as a significant personality factor independently associated with psychotic symptoms (Wald = 7.44, p<0.05, OR = 1.08, CI 95% 1.02-1.16) after controlling for age, gender and number of consumption substances. CONCLUSIONS:An association between high neuroticism scores and presence of psychotic symptoms induced by cocaine has been found, independently of other consumption variables. Personality dimensions should be evaluated in cocaine-dependent patients in order to detect high scores of neuroticism and warn patients about the risk of developing cocaine-induced psychotic symptoms