Val/Met BDNF as a genetic risk for a false sense of security in post-discharge suicide risk.

BACKGROUND: The time after discharge from psychiatric inpatient care is one of the most dangerous periods in terms of suicide risk. Predicting who is at higher risk could help with resource allocation to assure patients at high risk of suicide attempts are most closely followed. We previously showed that inpatients who improve their suicide ideation levels faster while in inpatient treatment are the ones with highest rates of post-discharge suicide. Here, we studied the possible genetic underpinnings associated with such risk. METHOD: We recorded the slope of suicide ideation recovery of 710 psychiatric inpatients from which we studied two genetic variants likely associated with suicide risk: The serotonin transporter variant 5-HTTLPR, and the BDNF gene variant Val66Met. RESULTS: We found that inpatients carrying the BDNF Met variant (hypothesized as conferring higher suicide risk) improved their suicide ideation scores faster than Val/Val carrying inpatients. No significant association was found for 5-HTTLPR. LIMITATIONS: The present sample was genetically homogenous, and future research should replicate these findings on a more diverse sample. CONCLUSIONS: In conclusion, we found a paradoxical result: Carrying the BDNF Met variant allows inpatients to improve faster, which was shown to confer higher risk at the post-discharge period. This may explain some inconsistencies in the literature in terms of the role of BDNF in suicide ideation and attempts.

Emotional self-regulation, impulsivity, 5-HTTLPR and tobacco use behavior among psychiatric inpatients.

BACKGROUND: While the serotonin transporter (SLC6A4) gene, 5-HTTLPR, interacts with the social environment to influence both emotional self-regulation and smoking behavior, less is known about interactions between emotional self-regulation and 5-HTTLPR or their joint influence on tobacco use. Here, we examined such interactions among psychiatric inpatients, the population with the highest rates of smoking. METHODS: Participants (506 adults) were psychiatric inpatients at The Menninger Clinic in Houston TX between 2012 and 16. Most were white (89%), male (55%), with a mean age of 32.3 years. Participants completed the Difficulties in Emotional Regulation Scale (DERS) at admission. We examined interactions with smoking among three DERS subscales and 5-HTTLPR, controlling for sex, race and age. RESULTS: Smoking rates were higher among those with the 5-HTTPLR L'L' genotype compared to peers carrying an S' allele (47.9% vs. 37.4%, respectively). Among S' allele carrying participants, impulse control difficulties (OR = 1.09; 95%CI: 1.03-1.14) and lack of emotion clarity (OR = 1.06; 95%CI: 1.00-1.11) increased risk for ever using tobacco, while accessing more ways to regulate emotion (OR = 0.95; 95%CI: 0.92-0.99) offered a protective effect against ever using tobacco. Neither demographic nor DERS covariates were associated with using tobacco among the L'L' group. LIMITATIONS: This ethnically homogenous sample limits generalizability and using a binary outcome can over-estimate a gene environment interaction effect. CONCLUSIONS: Emotional self-regulation exerts a stronger influence on using tobacco among carriers of an S' allele of 5-HTTLPR than peers with the L'L' genotype. Promoting emotional self-regulatory skills may have benefits for preventing tobacco use.

Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia: relationships with clinical phenotypes and cognitive deficits.

BACKGROUND: Schizophrenia patients have a higher prevalence of type 2 diabetes mellitus with impaired glucose tolerance (IGT) than normals. We examined the relationship between IGT and clinical phenotypes or cognitive deficits in first-episode, drug-naïve (FEDN) Han Chinese patients with schizophrenia. METHOD: A total of 175 in-patients were compared with 31 healthy controls on anthropometric measures and fasting plasma levels of glucose, insulin and lipids. They were also compared using a 75 g oral glucose tolerance test and the homeostasis model assessment of insulin resistance (HOMA-IR). Neurocognitive functioning was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). RESULTS: Of the patients, 24.5% had IGT compared with none of the controls, and they also had significantly higher levels of fasting blood glucose and 2-h glucose after an oral glucose load, and were more insulin resistant. Compared with those patients with normal glucose tolerance, the IGT patients were older, had a later age of onset, higher waist or hip circumference and body mass index, higher levels of low-density lipoprotein and triglycerides and higher insulin resistance. Furthermore, IGT patients had higher PANSS total and negative symptom subscale scores, but no greater cognitive impairment except on the emotional intelligence index of the MCCB. CONCLUSIONS: IGT occurs with greater frequency in FEDN schizophrenia, and shows association with demographic and anthropometric parameters, as well as with clinical symptoms but minimally with cognitive impairment during the early course of the disorder.

Animal Models and the Development of Vaccines to Treat Substance Use Disorders.

The development of pharmacotherapies for substance use disorders (SUDs) is a high priority in addiction research. At present, there are no approved pharmacotherapies for cocaine and methamphetamine use disorders, while treatments for nicotine and opioid use are moderately effective. Indeed, many of these treatments can cause adverse drug side effects and have poor medication compliance, which often results in increased drug relapse rates. An alternative to these traditional pharmacological interventions is immunotherapy or vaccines that can target substances associated with SUDs. In this chapter, we discuss the current knowledge on the efficacy of preclinical vaccines, particularly immunogens that target methamphetamine, cocaine, nicotine, or opioids to attenuate drug-induced behaviors in animal models of SUDs. We also review vaccines (and antibodies) against cocaine, nicotine, and methamphetamine that have been assessed in human clinical trials. While preclinical studies indicate that several vaccines show promise, these findings have not necessarily translated to the clinical population. Thus, continued effort to design more effective vaccine immunogens using SUD animal models is necessary in order to support the use of immunotherapy as a viable option for individuals with SUDs.

[A double-blind randomized placebo-controlled study of the efficacy of the combined treatment with naltrexone and guanfacine for relapse prevention in opiate dependence].

OBJECTIVE: Authors studied the effect of α-2-adrenoreceptor agonist guanfacine on replace prevention in opiate addicts. MATERIAL AND METHODS: Three hundred and one recently detoxified opiate addicts were randomized under the double-blind double-dummy conditions into one of four treatment groups: naltrexone 50 mg/day+guanfacine 1 mg/day (N+G), naltrexone+guanfacine placebo (N+GP), naltrexone placebo+guanfacine (NP+G), and double placebo (NP+GP). The primary outcome was retention in treatment. The secondary outcomes were perceived stress (Perceived Stress Scale) and craving. RESULTS: At the end of six months, 20 (26.7%) patients in the N+G group and 15 (19.7%) (p=0.26 to N+G) in N+GP group were retained in treatment compared to 5 (6.7%) in the NP+G group (p=0.002 to N+G group and p=0.017 to N+GP group) and 8 (10.7%) in the double placebo group (p=0.013 to N+G group). There is no significant difference in retention between the N+G group and N+GP group at the end of treatment. CONCLUSION: Guanfacine had significant craving and stress reducing effect. Naltrexone was more effective than placebo for relapse prevention in opioid dependent patients. The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone alone. Guanfacine moderately reduced both stress and craving.

A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study.

This study aimed to evaluate whether functional variants in the ankyrin repeat and kinase domain-containing 1 (ANKK1) gene and/or the dopamine receptor D2 (DRD2) gene modulate the subjective effects (reward or non-reward response to a stimulus) produced by cocaine administration. Cocaine-dependent participants (N = 47) were administered 40 mg of cocaine or placebo at time 0, and a subjective effects questionnaire (visual analog scale) was administered 15 min prior to cocaine administration, and at 5, 10, 15 and 20 min following administration. The influence of polymorphisms in the ANKK1 and DRD2 genes on subjective experience of cocaine in the laboratory was tested. Participants with a T allele of ANKK1 rs1800497 experienced greater subjective 'high' (P = 0.00006), 'any drug effect' (P = 0.0003) and 'like' (P = 0.0004) relative to the CC genotype group. Although the variant in the DRD2 gene was shown to be associated with subjective effects, linkage disequilibrium analysis revealed that this association was driven by the ANKK1 rs1800497 variant. A participant's ANKK1 genotype may identify individuals who are likely to experience greater positive subjective effects following cocaine exposure, including greater 'high' and 'like', and these individuals may have increased vulnerability to continue using cocaine or they may be at greater risk to relapse during periods of abstinence. However, these results are preliminary and replication is necessary to confirm these findings.

Pharmacogenetic randomized trial for cocaine abuse: disulfiram and α1A-adrenoceptor gene variation.

Disulfiram is a cocaine addiction pharmacotherapy that inhibits dopamine ß-hydroxylase (DßH) and reduces norepinephrine production. We examined whether a functional variant of the ADRA1A gene (Cys to Arg at codon 347 in exon 2, Cys347Arg) may enhance treatment response through decreased stimulation of this α1A-adrenoceptor, since antagonists of this receptor show promise in reducing cocaine use. Sixty-nine cocaine and opioid co-dependent (DSM-IV) subjects were stabilized on methadone for two weeks and subsequently randomized into disulfiram (250 mg/day, N=32) and placebo groups (N=37) for 10 weeks. We genotyped the ADRA1A gene polymorphism (rs1048101) and evaluated its role for increasing cocaine free urines in those subjects treated with disulfiram using repeated measures analysis of variance, corrected for population structure. The 47 patients who carried at least one T allele of rs1048101 (TT or TC genotype) reduced their cocaine positive urines from 84% to 56% on disulfiram (p=0.0001), while the 22 patients with the major allele CC genotype showed no disulfiram effect. This study indicates that a patient's ADRA1A genotype could be used to identify a subset of individuals for which disulfiram and, perhaps, other α1-adrenoceptor blockers may be an effective pharmacotherapy for cocaine dependence.

The alpha-1 adrenergic antagonist doxazosin for treatment of cocaine dependence: A pilot study.

BACKGROUND: Medications decreasing central noradrenergic activity have been associated with attenuation of cocaine effects. AIMS: This pilot study examined the efficacy of doxazosin versus placebo for reducing cocaine use in treatment-seeking cocaine dependent persons. METHODS: We screened 108 cocaine dependent subjects and assigned 35 participants to receive either doxazosin (8mg/day) or placebo for 13 weeks. Participants were titrated on the study medication according to two different schedules. During the initial phase of the study, patients were titrated onto the study medication over an 8-week period (DOX-slow). After reviewing data from our human laboratory study, a second phase was initiated, wherein titration was accelerated to a 4-week period (DOX-fast). All participants received weekly cognitive behavioral therapy. Urine toxicology was performed thrice weekly. RESULTS: Baseline subject characteristics were comparable. Thirty subjects entered the study: 8 subjects in DOX-slow, 9 subjects in DOX-fast, and 13 subjects in placebo. Total number of cocaine-negative urines was significantly increased in the DOX-fast group; and percentage of total cocaine-negative urines by group were 10% for DOX-slow group, 35% for DOX-fast group, and 14% for placebo (χ(2)=36.3, df=2, p<0.0001). The percentage of participants achieving two or more consecutive weeks of abstinence by group was 0% for DOX-slow group, 44% for DOX-fast group, and 7% for placebo (χ(2)=7.35, df=2, p<0.023). CONCLUSIONS: This pilot study suggests the potential efficacy of doxazosin when rapidly titrated in reducing cocaine use.

Cigarette smoking, psychopathology and cognitive function in first-episode drug-naive patients with schizophrenia: a case-control study.

BACKGROUND: Although patients with chronic schizophrenia have substantially higher smoking rates than either the general population or patients with other mental illnesses, drug-naive patients with a first episode of schizophrenia have received little systemic study. This study examined smoking rates, the association between smoking and symptom severity and cognitive function in Chinese first-episode schizophrenia (FES) patients using cross-sectional and case-control designs. METHOD: Two hundred and forty-four drug-naive FES patients and 256 healthy controls matched for gender, age and education completed the Fagerström Test for Nicotine Dependence (FTND) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Patients were also rated on the Positive and Negative Symptom Scale (PANSS). RESULTS: The rate and quantity of smoking were not significantly higher among FES patients compared to the general population. Among patients, smokers scored higher than non-smokers on the total PANSS and the positive symptom subscale scores. There were no significant associations between cognitive function and smoking in either FES patients or healthy controls. CONCLUSIONS: In contrast to studies in patients with chronic schizophrenia, drug-naive FES patients did not smoke more frequently than the general population. Furthermore, patients with psychotic disorders who smoked did not exhibit significant cognitive differences compared with those who did not smoke. However, smoking may have other detrimental effects on physical and mental health, for example on positive symptoms.

Modifying the role of serotonergic 5-HTTLPR and TPH2 variants on disulfiram treatment of cocaine addiction: a preliminary study.

Disulfiram is a cocaine pharmacotherapy that may act through increasing serotonin, benefiting patients with genetically low serotonin transporter levels (5-HTTLPR, S' allele carriers) and low serotonin synthesis (TPH2, A allele carriers). We stabilized 71 cocaine and opioid co-dependent patients on methadone for 2 weeks and randomized them into disulfiram and placebo groups for 10 weeks. We genotyped the SLC6A4 5-HTTLPR (rs4795541, rs25531) and TPH2 1125A>T (rs4290270) variants and evaluated their role in moderating disulfiram treatment for cocaine dependence. Cocaine-positive urines dropped from 78% to 54% for the disulfiram group and from 77% to 76% for the placebo group among the 5-HTTLPR S' allele carriers (F = 16.2; df = 1,301; P < 0.0001). TPH2 A allele carriers responded better to disulfiram than placebo (F = 16.0; df = 1,223; P < 0.0001). Patients with both an S' allele and a TPH2 A allele reduced cocaine urines from 71% to 53% on disulfiram and had no change on placebo (F = 21.6; df = 1,185; P < 0.00001).

Vaccines against drug abuse.

The currently available medications for the treatment of drug abuse have had only limited success. Anti-addiction vaccines, aimed at eliciting antibodies that block the pharmacological effects of drugs, have great potential for treating drug abuse. We review the status of two vaccines that are undergoing clinical trials (for cocaine and nicotine addiction) and two that are still in preclinical development (for methamphetamine and heroin addiction). We also outline the challenges and ethical concerns associated with the development of anti-addiction vaccines and their use as future therapeutics.

Differential effects of D1- and D2-like compounds on cocaine self-administration in Lewis and Fischer 344 inbred rats.

Genetic factors influence behavioral responses to cocaine as seen in comparisons of Lewis and Fischer 344 inbred rats. Lewis rats have lower D2-like receptor and Gi(alpha) levels in nucleus accumbens, an important area in behavioral responses to cocaine. This study assessed the effects of manipulating D2- and D1 levels pharmacologically in these strains. Experiment 1 investigated how the D2-like antagonist eticlopride (0.01-0.1 mg/kg), the D1-like antagonist SCH 23390 (0.005-0.05 mg/kg), the D2/D3 agonist quinpirole (0.001-0.1 mg/kg), and the partial D1 agonist SKF 38393 (0.1-10 mg/kg) affected responding for food under a fixed ratio 15 schedule. Quinpirole disrupted rates more readily in Lewis versus Fischer 344 rats. In experiment 2, the effects of these agents on cocaine discrimination (10 mg/kg) were examined. Quinpirole substituted and SCH 23390-attenuated cocaine discrimination in both strains. Doses of the drugs that did not disrupt responding in these experiments were tested in cocaine self-administration in experiment 3. Cocaine self-administration (0.25-1.0 mg/kg) was increased by eticlopride (0.03 mg/kg) in Lewis rats but had no effect in Fischer 344 rats, whereas SCH 23390 (0.01 mg/kg) led to greater increased cocaine self-administration in Fischer 344 versus Lewis rats. The dopamine agonists had differential effects on cocaine self-administration in the strains. Cocaine self-administration was decreased in Lewis rats and increased in Fischer 344 rats by SKF 38393 (1 mg/kg). These data show that manipulating D1- and D2-like receptor availability has strain-selective effects on the reinforcing, but not discriminative stimulus, effects of cocaine that are predicted by inherent differences in nucleus accumbens receptor populations.

Substance use disorders in patients with posttraumatic stress disorder: a review of the literature.

OBJECTIVE: Alcohol use disorders and other substance use disorders are extremely common among patients with posttraumatic stress disorder (PTSD). This article reviews studies pertaining to the epidemiology, clinical phenomenology, and pathophysiology of comorbid PTSD and substance use disorders. METHOD: Studies were identified by means of computerized and manual searches. The review of research on the pathophysiology of PTSD and substance use disorders was focused on studies of the hypothalamic-pituitary-adrenal axis and the noradrenergic system. RESULTS: High rates of comorbidity suggest that PTSD and substance use disorders are functionally related to one another. Most published data support a pathway whereby PTSD precedes substance abuse or dependence. Substances are initially used to modify PTSD symptoms. With the development of dependence, physiologic arousal resulting from substance withdrawal may exacerbate PTSD symptoms, thereby contributing to a relapse of substance use. Preclinical work has led to the proposal that in PTSD, corticotropin-releasing hormone and noradrenergic systems may interact such that the stress response is progressively augmented. Patients may use sedatives, hypnotics, or alcohol in an effort to interrupt this progressive augmentation. CONCLUSIONS: Vigorous control of withdrawal and PTSD-related arousal symptoms should be sought during detoxification of patients with comorbid PTSD and substance use disorders. Inclusion of patients with comorbid PTSD and substance use disorders in neurobiologic research and in clinical trials will be critical for development of effective treatments for this severely symptomatic patient population.

A discriminative two-lever test of dizocilpine's ability to reinstate ethanol-seeking behavior.

Because ethanol has N-methyl-D-aspartate (NMDA) antagonist effects, we tested whether dizocilpine, an NMDA antagonist, reinstates ethanol-seeking behavior. Rats were trained to lever-press for a 10% ethanol/2% sucrose (EtOH) or a 3% sucrose (Suc) solution using a two-lever (one lever active) procedure (FR2). After extinction, rats were injected with ethanol (0.5 g/kg). The EtOH group emitted more active than inactive lever presses and the Suc group showed minimal responding. Thus, ethanol reinstated ethanol-seeking behavior in a specific manner. In contrast, dizocilpine (0.175 mg/kg) increased responding on both levers in both groups suggesting a loss of discriminative control. Dizocilpine fails to reinstate ethanol-seeking behavior. These data also demonstrate the necessity of using a discriminative, two-lever test for drug reinstatement.

Neuroleptic use in the treatment of Post-Traumatic Stress Disorder.

BACKGROUND: There have been few studies of the use of neuroleptics in the treatment of Post-Traumatic Stress Disorder (PTSD). This study uses data from two large outcome studies to: (1) examine demographic and treatment characteristics associated with neuroleptic prescription in the treatment of PTSD, and (2) compare the outcomes of neuroleptic-treated patients with those not receiving neuroleptics. METHODS: A secondary analysis of an observational outcome study of 831 inpatients and 554 outpatients (all males) receiving treatment at the VA for combat-related PTSD was performed. Patients were classified as having either received neuroleptics during the following year or not. Sociodemographic characteristics, treatment and medication history and detailed information about PTSD symptoms were obtained at baseline and 12 months. First, the two groups were compared with respect to the demographic and clinical variables. We then conducted a series of separate paired t-tests to determine whether there was significant improvement from baseline to follow up in each group and a series of analyses of covariance that compared outcomes in the two groups, adjusting for baseline differences. RESULTS: Approximately 9% of inpatients and 10% of outpatients were treated with neuroleptics. Patients who received neuroleptics had both more psychiatric and more social impairment. They also demonstrated more severe PTSD (especially intrusive symptoms) despite having similar combat exposure. Outcomes after one year for the group treated with neuroleptics were not significantly different from the group not treated with neuroleptics. CONCLUSIONS: Neuroleptic use in the treatment of PTSD is targeted at more seriously ill patients and was not associated with substantial improvement.

Ethanol enhances naloxone sensitization and disrupts morphine discrimination--comparison to dizocilpine and pentobarbital: explanation of enhancing acute and attenuating chronic effects.

1. Ethanol affects ligand-gated ion channels as a positive modulator of gamma-aminobutyric acid (GABA(A)) receptor function and an N-methyl-D-aspartate (NMDA) antagonist. NMDA antagonists attenuate chronic drug effects. Accordingly, we found that ethanol decreased morphine dependence and locomotor sensitization. We now test whether ethanol alters sensitization to the disrupting effects of naloxone on schedule-controlled responding after morphine administration or affects the acute stimulus effects of morphine. 2. Groups of rats, trained to lever-press for food, were co-administered ethanol (1 g/kg; i.p.), the NMDA antagonist dizocilpine (DZ; 0.05 mg/kg; i.p.), the GABA(A) agonist pentobarbital (PB; 3 mg/kg i.p.), or vehicle with morphine (5 mg/kg s.c.). Separate groups received naloxone (0.1-1 mg/kg s.c.) 4-hrs later, prior to food sessions (FR15; 30 min) on three consecutive days. Ethanol enhanced the suppressive effects of higher naloxone doses on all three days. DZ and PB altered this behavior differentially by day and naloxone dose. 3. Next, we examined the effects of ethanol, DZ, PB, and naloxone (0.3 mg/kg; s.c.) on morphine discrimination. Rats, trained to discriminate morphine (3.2 mg/kg s.c.) from saline in a two-lever, food-reinforced procedure, were tested with morphine (0, 1-5.6 mg/kg) after vehicle and drug administrations. Naloxone blocked dose-related responding to morphine, demonstrating pharmacological specificity, and altered response rates. Both ethanol and DZ, but not PB, disrupted morphine-appropriate responding. 4. The paradox that ethanol and DZ attenuate chronic morphine effects while enhancing acute effects may reflect a temporal pattern of primary mu opiate receptor function followed by secondary NMDA-mediated processes induced by morphine administration.

Differential behavioral responses to cocaine are associated with dynamics of mesolimbic dopamine proteins in Lewis and Fischer 344 rats.

Differential behavioral and biochemical responses to drugs of abuse may reflect genetic makeup as suggested by studies of inbred Lewis (LEW) and Fischer 344 (F344) rats. We investigated locomotor activity, stereotypy signs, and levels of specific proteins in the nucleus accumbens (NAc) and ventral tegmental area (VTA) in these strains at baseline and following chronic administration of cocaine (30 mg/kg/day for 14 days). Using Western blot analysis, we replicated our previous findings of baseline strain differences and found lower levels of DeltaFosB immunoreactivity in NAc of F344 vs. LEW rats. F344 rats showed greater baseline locomotor activity, sniffing, and grooming compared to LEW rats. Chronic cocaine increased DeltaFosB levels in NAc in both strains, whereas adaptations in other proteins were induced in F344 rats only. These included reduced levels of tyrosine hydroxylase (TH) in NAc and increased TH and glial fibrillary acidic protein (GFAP) immunoreactivity in VTA. Chronic cocaine led to greater increases in overall stereotypy in F344 vs. LEW rats and decreased exploratory behaviors in LEW rats. Opposing effects by strain were seen in locomotor activity. Whereas F344 rats showed higher initial activity levels that decreased with cocaine exposure (tolerance), LEW rats showed increased activity over days (sensitization) with no strain differences seen at 14 days. Further, conditioned locomotor activation to vehicle injections was greater in F344 vs. LEW rats. These results suggest that behavioral responsiveness to chronic cocaine exposure may reflect dynamics of mesolimbic dopamine protein levels and demonstrate the role of genetic background in responsiveness to cocaine.