RESUMEN
BACKGROUND: The lifetime risk of suicide in patients with substance use disorder is five to ten times the risk in the general population. Critically, up to 19% of patients continue to think about and attempt suicide even after accessing treatment. Therefore, suicidality represents a significant clinical concern in patients struggling with substance use that warrants careful investigation of the factors involved. While most previous research has relied on limited cross-sectional designs, a growing number of prospective studies are improving our understanding of the factors involved. However, a systematic study of these factors has not yet been conducted. METHODS: The primary objective of this review and possible meta-analysis will be to identify key risk and protective factors for suicide ideation, attempt, and death in patients accessing substance use treatment, guided by current models of suicide. Secondary and tertiary objectives will be to obtain pooled effect sizes for the factors identified and to disaggregate factors for suicidality before and after treatment, and for suicidal thought versus action. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we will conduct an electronic search of the literature using the databases Embase, Medline, PsycINFO, and Web of Science. Two authors will independently screen studies based on pre-specified inclusion and exclusion criteria, extract relevant data, and assess study quality. Observational and randomized-controlled studies will be included, whereas case-studies and reviews will be excluded. We will extract data on risk and protective factors associated with suicide ideation, attempt (odds or risk ratios), and death (hazard ratio). Given sufficient data (> 5 studies), we will calculate pooled effects using comprehensive meta-analysis. DISCUSSION: This systematic review will contribute to our knowledge of risk and protective factors for suicidality in patients before and after treatment. Understanding these factors will help define areas of research for further investigation to ultimately inform risk assessment and prevention strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (reference number: CRD42018076260).
Asunto(s)
Trastornos Relacionados con Sustancias , Prevención del Suicidio , Suicidio , Causalidad , Humanos , Metaanálisis como Asunto , Factores Protectores , Proyectos de Investigación , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/psicología , Suicidio/psicología , Revisiones Sistemáticas como AsuntoRESUMEN
Sustained-release (SR) alprazolam may facilitate compliance with oral benzodiazepine treatment of panic disorders that currently requires doses administered three or four times daily. To compare the pharmacokinetic, psychomotor performance, and subjective effects of alprazolam SR (1.5 mg), bromazepam (3 mg taken three times daily), and lorazepam (1 mg taken three times daily), 13 male volunteers (aged 20-45 years) randomly received on four separate occasions one of these medications or placebo. Once before and 11 times after drug administration, the subjects were tested using psychomotor performance tests (manual tracking and digit-symbol substitution test [DSST]) and computerized questionnaires (such as the Tufts University Benzodiazepine Scale [TUBS], the Addiction Research Center Inventory, and the visual analog scales) to determine the subjective effects of the drugs. Blood samples for the determination of the plasma levels of the drugs were collected before and 17 times after the drug was administered. A peak plateau of plasma alprazolam began approximately 6 hours after the dose, which was later than the initial peaks for lorazepam and bromazepam (1-2 hours after the dose). Once this plateau had begun, alprazolam SR sustained that concentration better than did the other two formulations. Of the 10 measures on which the response averaged for the first 14 hours differed among drugs (p < 0.05), bromazepam differed from placebo on two measures, lorazepam on four (including DSST Performance and TUBS Sedation), and alprazolam SR on nine (including all four affected by lorazepam). Lorazepam and alprazolam, but not bromazepam, produced significantly more sedation than placebo. The doses of the three drugs were not equipotent in sedation and mood effects. None of the drugs tested differed from placebo on measures relevant to abuse liability.
Asunto(s)
Alprazolam/sangre , Ansiolíticos/sangre , Bromazepam/sangre , Lorazepam/sangre , Adulto , Afecto/efectos de los fármacos , Afecto/fisiología , Alprazolam/farmacología , Ansiolíticos/farmacología , Bromazepam/farmacología , Estudios Cruzados , Preparaciones de Acción Retardada , Método Doble Ciego , Humanos , Modelos Logísticos , Lorazepam/farmacología , Masculino , Persona de Mediana Edad , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiologíaRESUMEN
Drug abuse liability testing usually involves a subject population of individuals who are current or former drug abusers. To determine whether choosing subjects from a wider and more diverse population of nondrug abusers results in subjective response patterns that are pharmacologically associated with drug abuse liability, a series of studies were conducted using the prescription opiate hydromorphone and the barbiturate secobarbital to prescreen subjects before their acceptance into large multidrug, multidose abuse liability studies. The results of these prescreening studies show that there were some subjects who were not able to report consistently and reliably relevant drug effects, even though they received pharmacologically active doses as measured by objective indexes such as pupil diameter for the opiate study and psychomotor impairment for the barbiturate study. To test the consistency of these results, several of the subjects from the hydromorphone screening were retested with hydrocodone. The results demonstrate that subjects who were unable to report positive subjective effects of hydromorphone were also unable to respond appropriately to hydrocodone, and subjects who responded appropriately to hydromorphone in the prescreening study consistently responded to another opiate. Using this prescreening methodology has allowed sensitive and reliable data on the abuse liability of benzodiazepine agonists and partial agonists, barbiturates, carbamate compounds, amphetamines, selective serotonin reuptake inhibitors and prescription opiate compounds to be generated using a nondrug abusing population. In conclusion, due to the relative heterogeneity of a population of nondrug abusers compared with a drug abusing population, it is necessary to prescreen subjects for their ability to detect and report subjective drug effects, and to distinguish the effects of an active drug from those of placebo. Selecting subjects from this population has several advantages over selecting subjects from the drug abusing population that outweigh any inconvenience of this simple prescreening methodology.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Psicotrópicos/efectos adversos , Trastornos Relacionados con Sustancias/psicología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Proyectos de InvestigaciónRESUMEN
Dextromethorphan is a nonopioid antitussive metabolized by cytochrome P450 2D6 (CYP2D6) to an active metabolite, dextrorphan. CYP2D6 is polymorphically expressed in humans, with 5 to 10% of Caucasians being homozygous deficient for the active form of the enzyme. In a pilot study, the authors investigated the pharmacologic effects of dextromethorphan in individuals phenotyped and genotyped as extensive metabolizers (EMs, N = 4) and poor metabolizers (PMs, N = 2) of CYP2D6 substrates. Dextromethorphan doses ranged from 0 to 6 mg/kg based on individual subject tolerance. All EMs tolerated 3 to 6 mg/kg dextromethorphan, whereas PMs barely tolerated 3 mg/kg dextromethorphan and therefore received lower doses. As shown in previous studies, plasma kinetics show profound differences in dextromethorphan metabolism between EMs and PMs. Dextromethorphan produced qualitatively and quantitatively different objective and subjective effects in the two groups. Objectively, PMs had greater psychomotor impairment, as measured by a joystick tracking task, compared with EMs on 3 mg/kg dextromethorphan (mean performance +/- SE, 95+/-0.5% for EMs vs. 86+/-6% for PMs; p < 0.05). At this dose, EMs also reported greater abuse potential compared with PMs (p < 0.05), and PMs reported greater sedation and dysphoria compared with EMs (p < 0.01). These data provide preliminary evidence that dextrorphan contributes to dextromethorphan abuse liability, and therefore PMs may be less likely to abuse dextromethorphan.
Asunto(s)
Antitusígenos/farmacología , Citocromo P-450 CYP2D6/genética , Dextrometorfano/farmacología , Genotipo , Drogas Ilícitas/farmacología , Polimorfismo Genético/genética , Adulto , Antitusígenos/farmacocinética , Dextrometorfano/farmacocinética , Relación Dosis-Respuesta a Droga , Humanos , Drogas Ilícitas/farmacocinética , Masculino , Tasa de Depuración Metabólica , Proyectos PilotoRESUMEN
Sertraline is an effective antidepressant acting as a selective serotonin reuptake inhibitor. The subjective and behavioral effects of sertraline were studied and compared with the effects of alprazolam and dextroamphetamine in a within-subject, randomized, double-blind study in 20 volunteers aged 18 to 46 years. These subjects were experienced but nondependent users of central nervous system depressants who had the ability to reliably distinguish secobarbital, 150 mg, from placebo and to report positive subjective effects of secobarbital in an experimental setting. The following drug conditions were tested: sertraline, 100 and 200 mg; alprazolam, 1 mg; dextroamphetamine, 10 mg; and placebo. Drug effects were assessed with an objective test of psychomotor performance, subject-rated questionnaires, and observer-rated scales. Both alprazolam and dextroamphetamine were distinguishable from placebo on most measures, but sertraline produced effects discernable from placebo on only a few measures. At 1 hour postdrug administration, dextroamphetamine and alprazolam produced positive effects on several measures of elation, euphoria, and drug liking greater than placebo and both doses of sertraline. In contrast, sertraline produced higher scores on measures of dysphoria and physical unpleasantness than did the other drug conditions. Observer ratings of satisfaction with the drug and other pharmacologic effects were consistent with these findings. Results from this study indicate that sertraline, at the doses tested, does not possess the behavioral effects profile considered to be indicative of abuse potential when compared with alprazolam and dextroamphetamine.
Asunto(s)
1-Naftilamina/análogos & derivados , Alprazolam , Actitud , Dextroanfetamina , Inhibidores Selectivos de la Recaptación de Serotonina , Trastornos Relacionados con Sustancias/psicología , Adolescente , Adulto , Nivel de Alerta/efectos de los fármacos , Atención/efectos de los fármacos , Método Doble Ciego , Euforia/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Desempeño Psicomotor/efectos de los fármacos , Factores de Riesgo , Secobarbital , SertralinaRESUMEN
OBJECTIVES: To assess the pharmacologic effects and abuse liability of bretazenil, a partial benzodiazepine agonist, and compare them to the short-term effects of diazepam and alprazolam over a range of doses. METHODS: This was a placebo, within-subject, randomized, double-blind study conducted in 28 male volunteers. They were experienced but nondependent users of central nervous system depressants who had the ability to reliably distinguish 150 mg secobarbital from placebo and to report positive subjective effects. Subjects randomly received placebo and the two middle doses of diazepam, bretazenil, and alprazolam for the first 7 days of the study and, depending on their clinical response, received either the highest or the lowest dose of each drug for the remaining 3 days. Pharmacologic effects were assessed by use of objective tests (e.g., psychomotor performance), subject-rated questionnaires (e.g., Profile of Mood States), and observer-rated scales. RESULTS: All three drugs were clearly distinguishable from placebo on most measures. Diazepam and alprazolam produced dose-related psychomotor and memory impairment, whereas bretazenil produced a flatter slope. Both alprazolam and diazepam produced dose-dependent increases in subject and observer-rated sedation and liking, whereas bretazenil showed increases compared with placebo, but these effects were not dose dependent. CONCLUSIONS: Results from the study supported the view that bretazenil may have a partial agonist pharmacologic profile. Scores on subjective effects scales considered important for abuse liability assessment suggest a lower abuse liability of bretazenil than diazepam and alprazolam.