Catechol-O-Methyltransferase Activity in Individuals with Substance Use Disorders: A Case Control Study

Background Impulsivity and substance use disorders (SUD) can be related to the same environmental factors. In this study, we intended to evaluate the dopaminergic function in imprisoned SUD offenders through the determination of s-COMT activity. Methods The study included 46 male individuals from a Portuguese penal institution. The participants were assessed through a battery of standardised instruments: Psychopathy Checklist-Revised (PCL-R), Barratt Impulsivity Scale Version 11 (BIS-11), and the European version of the Addiction Severity Index (EuropASI). s-COMT erythrocyte activity was evaluated. Results Overall, 73.9% (n=34) of the individuals had Antisocial Personality Disorder (ASPD) and 58.7% (n=27) presented SUDs. We evidenced, for the first time, that, in SUD individuals, s-COMT activity is correlated with the severity of drug dependence (EuropASI) (p<0.05), and with BIS-11 factors self-control (p<0.0001) and non-planning (p=0.002). Conclusions This study opens new perspectives regarding the pharmacological intervention on drug dependence through the interference on dopamine pathways.

The Role of Serotonin in the Development of Psychiatric Disorders: Studies on Drug Dependence and Anxiety-like Behaviour Following the Genetic Reduction of the Serotonin Transporter

<p>Rationale: Given the high prevalence and large burden of psychiatric disorders it is imperative to determine the underling etiology in order for better understanding and treatment. The neurotransmitter serotonin (5-HT) has been associated with mental disorders in humans both pharmacologically and genetically. Individuals with the short-allele of a prominent polymorphism within the 5-HT transporter (SERT) show increased incidence of mood disorders and drug dependence. However, whether or not dysregulation in the 5-HT system causes, or is just associated with, psychiatric disorders is impossible to determine from human studies alone. Consequently, it is imperative to employ an animal model of down-regulated SERT function. To better understand the role of 5-HT in drug dependence, the rat’s behavioural response to the psychostimulant (±) 3, 4-methylenedioxymethamphetamine (MDMA), a preferentially serotonergically mediated drug, was assessed. Finally, the ability to rescue the anxiety-like phenotype in the SERT-/- rat by altering extracellular 5-HT during early development was also evaluated. Objective: The primary objective of the current thesis was to determine whether dysregulation of 5-HT is directly linked to the occurrence of psychiatric disorders, particularly drug dependence and anxiety. Methods: A model of down-regulated SERT function, the SERT knock-out (SERT-/-) rat, was used for all experiments in order to determine a causal relationship between 5-HT dysregulation and psychiatric disorders. In Chapter 2, the response of the SERT-/- rats to various tasks usually disrupted by MDMA was assessed. In Chapter 3, the sensitivity of the SERT-/- rats to the reinforcing effects of MDMA was determined using the self-administration paradigm. Finally, in Chapter 4, whether the anxiety-like behaviour of the SERT-/- rat could be rescued through normalising excessive extracellular 5-HT neonatally was assessed. An attempt was also made to determine a mechanism by which 5-HT dysregulation could alter behaviour. To this end, gene expression previously found to be up- or down-regulated in the SERT-/- rat was assessed in the neonatally treated rats. Results: The results of Chapter 2 indicated the SERT is necessary for MDMA’s disruption of startle habituation but not its psychomotor effects. Moreover, for those rats that could discriminate low dose MDMA from saline, genetic removal of the SERT resulted in the inability to discriminate MDMA from amphetamine, implying that, in these rats, MDMA was now subjectively indistinguishable from amphetamine. Indeed, this alteration also resulted in enhanced sensitivity to the reinforcing properties of MDMA, giving MDMA the qualities of a traditional psychostimulant in SERT-/- rats (Chapter 3). Finally, lowering the excessive 5-HT during neonatal development in SERT-/- rats led to a rescue of mild, but not high, anxiety-like behaviour in males. However, mRNA levels of long 3’NTR BDNF and 5-HT1a, genes associated with neurodevelopment, remained unchanged across genotypes and treatment groups (Chapter 4). Conclusions: Genetic removal of the 5-HT transporter results in an altered behavioural response to MDMA, in particular an increased sensitivity to its reinforcing properties. However, while the genetic removal of the SERT results in enhanced extracellular 5-HT, the pathological phenotypes present in this rat are likely due to this increase occurring in early development, not its continued presence in adulthood. Overall, these findings contribute to the growing body of literature indicating that enhanced brain 5-HT during early development can lead to pathological behaviour in adulthood.</p>

The Role of Serotonin in the Development of Psychiatric Disorders: Studies on Drug Dependence and Anxiety-like Behaviour Following the Genetic Reduction of the Serotonin Transporter

<p>Rationale: Given the high prevalence and large burden of psychiatric disorders it is imperative to determine the underling etiology in order for better understanding and treatment. The neurotransmitter serotonin (5-HT) has been associated with mental disorders in humans both pharmacologically and genetically. Individuals with the short-allele of a prominent polymorphism within the 5-HT transporter (SERT) show increased incidence of mood disorders and drug dependence. However, whether or not dysregulation in the 5-HT system causes, or is just associated with, psychiatric disorders is impossible to determine from human studies alone. Consequently, it is imperative to employ an animal model of down-regulated SERT function. To better understand the role of 5-HT in drug dependence, the rat’s behavioural response to the psychostimulant (±) 3, 4-methylenedioxymethamphetamine (MDMA), a preferentially serotonergically mediated drug, was assessed. Finally, the ability to rescue the anxiety-like phenotype in the SERT-/- rat by altering extracellular 5-HT during early development was also evaluated. Objective: The primary objective of the current thesis was to determine whether dysregulation of 5-HT is directly linked to the occurrence of psychiatric disorders, particularly drug dependence and anxiety. Methods: A model of down-regulated SERT function, the SERT knock-out (SERT-/-) rat, was used for all experiments in order to determine a causal relationship between 5-HT dysregulation and psychiatric disorders. In Chapter 2, the response of the SERT-/- rats to various tasks usually disrupted by MDMA was assessed. In Chapter 3, the sensitivity of the SERT-/- rats to the reinforcing effects of MDMA was determined using the self-administration paradigm. Finally, in Chapter 4, whether the anxiety-like behaviour of the SERT-/- rat could be rescued through normalising excessive extracellular 5-HT neonatally was assessed. An attempt was also made to determine a mechanism by which 5-HT dysregulation could alter behaviour. To this end, gene expression previously found to be up- or down-regulated in the SERT-/- rat was assessed in the neonatally treated rats. Results: The results of Chapter 2 indicated the SERT is necessary for MDMA’s disruption of startle habituation but not its psychomotor effects. Moreover, for those rats that could discriminate low dose MDMA from saline, genetic removal of the SERT resulted in the inability to discriminate MDMA from amphetamine, implying that, in these rats, MDMA was now subjectively indistinguishable from amphetamine. Indeed, this alteration also resulted in enhanced sensitivity to the reinforcing properties of MDMA, giving MDMA the qualities of a traditional psychostimulant in SERT-/- rats (Chapter 3). Finally, lowering the excessive 5-HT during neonatal development in SERT-/- rats led to a rescue of mild, but not high, anxiety-like behaviour in males. However, mRNA levels of long 3’NTR BDNF and 5-HT1a, genes associated with neurodevelopment, remained unchanged across genotypes and treatment groups (Chapter 4). Conclusions: Genetic removal of the 5-HT transporter results in an altered behavioural response to MDMA, in particular an increased sensitivity to its reinforcing properties. However, while the genetic removal of the SERT results in enhanced extracellular 5-HT, the pathological phenotypes present in this rat are likely due to this increase occurring in early development, not its continued presence in adulthood. Overall, these findings contribute to the growing body of literature indicating that enhanced brain 5-HT during early development can lead to pathological behaviour in adulthood.</p>

Comorbidity between mood and substance-related disorders: A systematic review and meta-analysis

Background and Objectives: Evidence indicates that mood disorders often co-occur with substance-related disorders. However, pooling comorbidity estimates can be challenging due to heterogeneity in diagnostic criteria and in the overall study design. The aim of this study was to systematically review and, where appropriate, meta-analyse estimates related to the pairwise comorbidity between mood disorders and substance-related disorders, after sorting these estimates by various study designs. Methods: We searched PubMed (MEDLINE), Embase, CINAHL and Web of Science for publications between 1980 and 2017 regardless of geographical location and language. We meta-analysed estimates from original articles in 4 broadly defined mood and 35 substance-related disorders. Results: After multiple eligibility steps, we included 120 studies for quantitative analysis. In general, regardless of variations in diagnosis type, temporal order or use of adjustments, there was substantial comorbidity between mood and substance-related disorders. We found a sixfold elevated risk between broadly defined mood disorder and drug dependence (odds ratio = 5.7) and fivefold risk between depression and cannabis dependence (odds ratio = 4.9) while the highest pooled estimate, based on period prevalence risk, was found between broadly defined dysthymic disorder and drug dependence (odds ratio = 11.3). Based on 56 separate meta-analyses, all pooled odds ratios were above 1, and 46 were significantly greater than 1 (i.e. the 95% confidence intervals did not include 1). Conclusion: This review found robust and consistent evidence of an increased risk of comorbidity between many combinations of mood and substance-related disorders. We also identified a number of under-researched mood and substance-related disorders, suitable for future scrutiny. This review reinforces the need for clinicians to remain vigilant in order to promptly identify and treat these common types of comorbidity.

Development and Psychometric Properties of the Synthetic Drug Dependence Scale in a Chinese Sample

Objective: In contrast to the drug situation in the rest of the world, synthetic drugs, rather than traditional drugs, have been the dominant abused drugs in China since 2019. However, the public misconception that synthetic drugs are not as addictive as traditional drugs, such as opioids and the scarcity of specific measurement instruments, have hindered the clinical diagnosis and treatment of synthetic drug abusers, thus the development of a localized instrument to evaluate dependence on synthetic drugs is in urgently needed.Method: Using a sample of 618 Chinese synthetic drug abusers (Mean age = 34.69 years; 44.17% female), the present study developed and examined the psychometric properties of a self-reporting instrument, the Synthetic Drug Dependence Scale (SDDS), which consists of four subscales: physical dependence, psychological dependence, health injury, and social function injury.Results: The SDDS revealed a three-factor model structure (weighted root mean square residual (WRMR) = 0.876, comparative fit index (CFI) = 0.965, Tucker–Lewis index (TLI) = 0.953, and Root mean square error of approximation (RMSEA) = 0.070), with good internal consistency (composite reliability = 0.912, alfa = 0.801) and convergent validity. Elevated scores on the SDDS were associated with a higher level of reward sensitivity, punishment sensitivity, and stronger impulsivity. Interestingly, psychological dependence was the only significant predictor (p &lt; 0.05) of criterion variables compared with the other three subscales, implying the important role of psychological factors in synthetic drugs dependence. Adequate measurement equivalence across sex, age (18–30 and 31–57 years old), and employment group (employed and unemployed) was also established.Conclusion: The SDDS appears to be an effective and reliable instrument that could be used to further investigate the characteristics of synthetic and traditional drug dependence, promoting a deeper understanding of the physical and psychological roles in drug dependence.

Facilitators and Barriers to Health Seeking among People Who Use Drugs in the Sunyani Municipality of Ghana: An Exploratory Study

Drug use is one of the global public health issues, and its accompanying disorders have consequences on people’s mental, physical, and environmental health. Nevertheless, the majority of people who use drugs have never been treated for drug dependence and other health conditions whilst others discontinue their treatment for drug use disorder. Using the health belief model, the study aimed at exploring facilitators and barriers to health-seeking among people who use drugs in the Sunyani Municipality of Ghana. A descriptive study design was used, employing a qualitative approach. In-depth interviews were conducted with a total of 22 participants, including two key informants (male and female). The first group of participants was recruited from the ghetto (an area in the municipality where people who use drugs are usually located). The other group of participants was recruited using hospital-based records. The interview data were transcribed, coded, and analysed for the generation of themes with the aid of Nvivo version 12 pro. The results showed that people who use drugs face health challenges such as drug dependence, malaria, lungs and breathing complications, cardiovascular complications, and skin complications. People who use drugs experienced poor perceived quality of life and low health status. Health-seeking behaviours of interviewees were influenced by the perceived benefit, perceived severity, cues to action, among others. Multiple sources of healthcare were used by the people who use drugs. Whereas ease of communication, perceived severity, benefit, among others were facilitators to their health-seeking behaviours, cost, dwindling social support, lack of knowledge of the condition, and fear of arrest by law enforcement agencies also served as barriers to seeking healthcare at the orthodox health facilities. This paper suggests a holistic approach to help improve the health and health-seeking behaviours of people who use drugs. The researchers wish to indicate that an earlier version of this manuscript has been presented at the University of Ghana as a thesis.

Change of the Pattern of the Demographic Characteristics of the Patients with Endocarditis: Clinical Case of Infectious Endocarditis in Man with Injectible Drug Dependence, Complicated with Pneumonia and Peripheral Necroses of Feet, Arms, Nose (Own Clinical Observations and Experience of Education in State and English Language)

Infectious endocarditis is multisystem disease, which is the result of the infection (usually bacterial) of endocardial heart surface. Despite of the latest medical achievements in diagnostics and treatment, infectious endocarditis is still a disease with high mortality rate and severe complications. During last decades in developed countries there are obvious changes of demographic characteristics of the patients with infectious endocarditis, namely increasing of aged patients with degenerative valvular diseases, of patients with anamnesis of invasive manipulations and procedures. Beside with well known risk factors (artificial valves and implanted heart devices), there are increasing roles of injectible drug-dependence, human immunodeficiency virus and wide contact with health protection system as predisposing factors for infectious endocarditis. The article contains literature data of the main populational risk groups of infectious endocarditis. Clinical case of severe (fatal) infectious endocarditis in patient with injectible drug dependence is submitted. Special features of the case are peripheral dry necroses of feet, arms, nose, which are very close to the description of symmetrical peripheral gangrene. This rare disorder was first described by Hutchinson in 1891 in 37-year old man, who had gangrene of fingers, hands and ears after shock. Symmetrical peripheral gangrene can be induced by different infection and non-inflection causes. The majority of these cases are connected to the treatment of cardiogenic shock with disseminated intravascular coagulation. Submitted description of the case of symmetrical peripheral gangrene in patient with infectious endocarditis will be useful for different medical care specialists as a reminder of the necessity of constant monitoring of the skin color of the distal parts of the limbs in severe sick patients.