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.

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.

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.

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.

A 2.5-year follow-up of depression, life crises, and treatment effects on abstinence among opioid addicts.

Follow-up studies have suggested that treatment increases addicts' likelihood of remaining abstinent and that depression and life crises are associated with decreased abstinence. An important issue is to what extent receiving treatment can ameliorate psychosocial risk factors such as life crises and depression and decrease ex-addicts' vulnerability to continued drug abuse. In our 2.5-year follow-up of 268 opiate addicts, drug abuse treatment was generally associated with increased abstinence, and life crises and depression were significant risk factors for continued drug abuse. The impact of these risk factors, however, was ameliorated by drug abuse treatment. Although life crises had a greater impact than depression, these two risk factors had additive effects in increasing the risk for continued drug abuse. Among the types of life crises, arguments and losses ("exits") had very strong additive effects with depression as predictors of drug abuse.

Pharmacotherapy for cocaine-abusing methadone-maintained patients using amantadine or desipramine.

In a double-blind, placebo-controlled 12-week randomized clinical trial, we compared amantadine hydrochloride (300 mg/d; n = 33), desipramine hydrochloride (150 mg/d; n = 30), and placebo (n = 31) in the treatment of cocaine-abusing methadone-maintained patients. Treatment retention and medication compliance were excellent, with more than 75% of the patients completing the full 12-week trial. Although reported cocaine abuse was significantly lower in the medicated groups compared with the placebo group at week 4, this difference became nonsignificant at week 8, and no difference was found in cocaine-free urine samples. Future studies of amantadine and desipramine treatment in these patients should consider alternatives to methadone hydrochloride, such as buprenorphine hydrochloride, and the selection of more homogeneous patient subgroups, such as depressed cocaine abusers.

A 2.5-year follow-up of cocaine use among treated opioid addicts. Have our treatments helped?

During a 2.5-year follow-up study of opioid addicts, we found that cocaine abuse had become an increasing and major problem through 1983. Cocaine abuse had only minimally declined during the follow-up period despite treatment, and the number of opioid addicts with at least weekly cocaine abuse had doubled. The clear effect of methadone maintenance treatment in reducing opioid abuse was not evident for cocaine abuse. During the follow-up period, more cocaine use was reported by the methadone-treated subjects than by those undergoing detoxification only. Prognostically, cocaine users were more likely to be nonwhites and men. Subjects who increased their cocaine use during the follow-up period were more likely to have depressive disorders and more likely to be found among methadone- and "drug-free"-treated subjects than among detoxification subjects. Thus, among methadone- and drug-free-treated subjects, depression appeared to be a risk factor for escalating cocaine abuse; this risk factor may benefit from specific interventions.

Buprenorphine vs methadone maintenance treatment for concurrent opioid dependence and cocaine abuse.

BACKGROUND: Buprenorphine, a partial mu-agonist and kappa-antagonist, has been proposed as an alternative to methadone for maintenance treatment of opioid dependence, especially for patients with concurrent cocaine dependence or abuse. This study evaluated whether higher maintenance doses of buprenorphine and methadone are superior to lower doses for reducing illicit opioid use and whether buprenorphine is superior to methadone for reducing cocaine use. METHODS: A total of 116 subjects were randomly assigned to 1 of 4 maintenance treatment groups involving higher or lower daily doses of sublingual buprenorphine (12 or 4 mg) or methadone (65 or 20 mg) in a double-blind, 24-week clinical trial. Outcome measures included retention in treatment and illicit opioid and cocaine use as determined by urine toxicology testing and self-report. RESULTS: There were significant effects of maintenance treatment on rates of illicit opioid use, but no significant differences in treatment retention or the rates of cocaine use. The rates of opioid-positive toxicology tests were lowest for treatment with 65 mg of methadone (45%), followed by 12 mg of buprenorphine (58%), 20 mg of methadone (72%), and 4 mg of buprenorphine (77%), with significant contrasts found between 65 mg of methadone and both lower-dose treatments and between 12 mg of buprenorphine and both lower-dose treatments. CONCLUSIONS: The results support the superiority of higher daily buprenorphine and methadone maintenance doses vs lower doses for reducing illicit opioid use, but the results do not support the superiority of buprenorphine compared with methadone for reducing cocaine use.

Desipramine in opioid-dependent cocaine abusers maintained on buprenorphine vs methadone.

BACKGROUND: Cocaine abuse occurs in 40% to 60% of patients entering opioid maintenance treatment, and effective pharmacotherapies are needed for this combined dependence. METHODS: This 13-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy of desipramine hydrochloride (0 or 150 mg/d) plus buprenorphine hydrochloride (12 mg/d) or methadone hydrochloride (65 mg/d) in 180 opioid-dependent cocaine abusers (124 men, 56 women). Supervised urine samples were obtained thrice weekly, and self-reported cocaine and heroin use was reported once weekly. Desipramine plasma levels were determined at weeks 4 and 10. RESULTS: In men, opioid abstinence was increased more rapidly over time when treated with methadone than with buprenorphine, whereas cocaine abstinence was increased more with buprenorphine than with methadone. In women, opioid abstinence was increased the least rapidly when treated with buprenorphine plus placebo, while cocaine abstinence was increased more rapidly over time when treated with methadone than with buprenorphine. Regardless of sex or opioid medication, desipramine increased opioid and cocaine abstinence more rapidly over time than placebo. Self-reported opioid use confirmed these findings. Desipramine plasma levels were higher in women than in men, particularly those on buprenorphine maintenance. Higher desipramine plasma levels were associated with greater opioid, but not cocaine, abstinence. CONCLUSIONS: Desipramine may be a useful adjunctive medication in facilitating opioid and cocaine abstinence in opioid-maintained patients. The efficacy of opioid medications to treat opioid or cocaine dependence may differ by sex. These findings highlight the importance of including sex as a factor when examining treatment outcome in these types of trials.

Prognostic significance of psychopathology in treated opiate addicts. A 2.5-year follow-up study.

Two different methods for assessing psychopathology in opiate addicts were compared as predictors of long-term treatment outcome: (1) categorical psychiatric diagnosis using the Schedule for Affective Disorders and Schizophrenia--Lifetime Version and the Research Diagnostic Criteria and (2) global rating of psychiatric impairment using the Psychiatric Severity scale of the Addiction Severity Index (ASI). Follow-up interviews were completed 2.5 years after treatment seeking in 76% of a sample of 361 opiate addicts. Five dimensions of treatment outcome were assessed, including current functioning, psychosocial adjustment, substance use impairment, legal problems, and medical disability. Most lifetime psychiatric disorders with a prevalence of greater than 10% were significantly related to the outcome dimensions of current functioning and/or psychosocial adjustment and were unrelated to substance use impairment, legal problems, and medical disability. The ASI Psychiatric Severity rating more robustly predicted poorer functioning in the same two areas and less severe legal problems. While controlling for ASI Psychiatric Severity, the only Research Diagnostic Criteria diagnosis that remained significantly related to treatment outcome was major depression, suggesting that, as regards their prognostic characteristics, the other diagnoses are accounted for by a global underlying severity dimension.

Noradrenergic dysregulation during discontinuation of cocaine use in addicts.

BACKGROUND: The primary objective of the study was to prospectively determine possible noradrenergic dysregulation in cocaine addicts by assessing biochemical, behavioral, and cardiovascular responses to intravenous yohimbine hydrochloride during early and late discontinuation of cocaine use. METHODS: Twelve male and two female hospitalized cocaine-dependent subjects (mean +/- SD age, 30.9 +/- 7.3 years) who were not seeking primary treatment for addiction participated voluntarily for monetary remuneration. Following an initial test dose of intranasal cocaine, 2 mg/kg, cocaine addicts received single-blind, monitored cocaine insufflation, 2 mg/kg three times each day, for 3 consecutive days. One to two days (early discontinuation) and 15 to 16 days (late discontinuation) after the last dose of cocaine, subjects received double-blind, randomized intravenous infusions of yohimbine hydrochloride, 0.4 mg/kg, or placebo. Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and plasma cortisol levels, anxiety-related symptoms on clinician- and subject-rated scales, blood pressure, and heart rate were measured throughout each test day. Ten of 14 subjects completed the entire study. RESULTS: Subjects had a significantly greater placebo-corrected MHPG response to yohimbine during early compared with late discontinuation. Subjects rated themselves significantly more nervous following yohimbine administration during early compared with late discontinuation. Seventy-one percent of subjects experienced a yohimbine-induced panic attack during early discontinuation compared with none during late discontinuation. CONCLUSIONS: The results of this study provide evidence of an underlying dysregulation in noradrenergic function and a vulnerability to panic anxiety during early discontinuation of cocaine use in addicts. Additional investigations of noradrenergic function appear warranted to further clarify derangements associated with cocaine addiction.

Psychiatric disorders in relatives of probands with opiate addiction.

Previous research has documented high rates of major depression and antisocial personality in opiate addicts. This study was designed to investigate the relationship of dual diagnosis in opiate-addicted probands to family history of psychiatric disorders and substance use disorders in biological relatives. Psychiatric disorders and substance use disorders were evaluated using direct interview and family history in a sample of 877 first-degree relatives of 201 opiate addicts and 360 relatives of 82 normal controls. Results indicate that (1) compared with relatives of normal subjects, opiate addicts' relatives had substantially higher rates of alcoholism, drug abuse, depression, and antisocial personality; (2) relatives of depressed opiate-addicted probands had elevated rates of major depression and anxiety disorders but not of other disorders, suggesting the validity of subtyping opiate addicts by the presence or absence of major depression; and (3) in contrast, relatives of antisocial opiate addicts had rates of disorders that were not significantly different from those of relatives of opiate addicts without antisocial personality. Implications of these findings for the classification and treatment of substance abuse are discussed.

Desipramine facilitation of initial cocaine abstinence.

We conducted a double-blind, random assignment, six-week comparison of desipramine hydrochloride (n = 24), lithium carbonate (n = 24), and placebo (n = 24) treatments for cocaine dependence. Subjects were 72 outpatient cocaine abusers who met DSM-III-R dependence criteria for cocaine but not for other substance abuse. Subjects in each treatment group were similar in history of cocaine and other substance abuse, cocaine craving, sociodemographics, and other psychiatric comorbidity. Desipramine, compared with both other treatments, substantially decreased cocaine use. Lithium treatment outcome did not differ from that of placebo. Desipramine-treated subjects attained contiguous periods of abstinence substantially more frequently than subjects receiving lithium or placebo. Fifty-nine percent of the desipramine-treated subjects were abstinent for at least three to four consecutive weeks during the six-week study period, compared with 17% for placebo and 25% for lithium. Cocaine craving reductions were also substantially greater in the desipramine-treated subjects. Establishment of initial abstinence is the first stage in recovery from cocaine dependence. Our findings indicate that desipramine is an effective general treatment, for this first treatment stage, in actively cocaine-dependent outpatients.

A randomized controlled trial of auricular acupuncture for cocaine dependence.

BACKGROUND: Partly because of a lack of a conventional, effective treatment for cocaine addiction, auricular acupuncture is used to treat this disorder in numerous drug treatment facilities across the country for both primary cocaine-dependent and opiate-dependent populations. OBJECTIVE: To evaluate the effectiveness of auricular acupuncture for the treatment of cocaine addiction. METHODS: Eighty-two cocaine-dependent, methadone-maintained patients were randomly assigned to 1 of 3 conditions: auricular acupuncture, a needle-insertion control condition, or a no-needle relaxation control. Treatment sessions were provided 5 times weekly for 8 weeks. The primary outcome was cocaine use assessed by 3-times-weekly urine toxicology screens. RESULTS: Longitudinal analysis of the urine data for the intent-to-treat sample showed that patients assigned to acupuncture were significantly more likely to provide cocaine-negative urine samples relative to both the relaxation control (odds ratio, 3.41; 95% confidence interval, 1.33-8.72; P =. 01) and the needle-insertion control (odds ratio, 2.40; 95% confidence interval, 1.00-5.75; P =.05). CONCLUSIONS: Findings from the current study suggest that acupuncture shows promise for the treatment of cocaine dependence. Further investigation of this treatment modality appears to be warranted.

Beta endorphin levels during heroin, methadone, buprenorphine, and naloxone challenges: preliminary findings.

Beta endorphin (BE) is a polypeptide agonist for the brain's endogenous opioid system. Levels of BE are elevated by opioid antagonists such as naloxone and depressed by short-acting agonists such as heroin and morphine; they become normalized during steady-state methadone. Buprenorphine (BUP) is a partial opioid agonist whose effects on BE levels were examined in six former heroin addicts and 14 methadone-maintained patients before and after being switched to sublingual BUP 2 mg daily for 1 month. In six former methadone-treated subjects BE levels also were measured after stopping BUP and after naloxone challenge. Levels of BE were not significantly lower in subjects started on BUP after stopping heroin (n = 6) (8.0 versus 8.1 ng/ml) or in subjects started on BUP after stopping methadone (n = 14) (11.6 vs 15.6 ng/ml). However, BE levels were lower on BUP than after naloxone challenge (n = 6) (7.0 versus 34.9 ng/ml). Levels of BE did not significantly change between the first 2 weeks ("early") and "later," although BE levels on methadone significantly correlated with BE levels on BUP in the "early" but not the "later" phase. The BE levels on BUP also did not differ from BE levels of unmedicated normals.

Buprenorphine: dose-related effects on cocaine and opioid use in cocaine-abusing opioid-dependent humans.

Fifteen subjects dependent on both opioids and cocaine completed an ascending and tapering schedule of buprenorphine dosing, with maintenance for 21 days at each dose of buprenorphine (4, 8, 12, 16 mg sublingual daily) during both ascending and tapering phases. Higher doses of buprenorphine led to greater reductions in opioid use: 64.7% of subjects were opioid abstinent for 3 weeks at the 16-mg dose compared to 27.3% at the 4-mg ascending dose. The proportion of cocaine-positive urine toxicologies was significantly lower during buprenorphine tapering (12 mg, 8 mg, 4 mg) compared to ascending doses up to 8 mg, with intermediate results at 12 mg and 16 mg during the ascending phase (F value = 6.6, df = 8,813, p < 0.001). Self-reported days, times, and quantity of cocaine used per week showed a similar pattern of intermediate reductions at the 12-mg and 16-mg dose during the ascending phase and significantly reduced values during the descending schedule. There were no significant buprenorphine dose effects on cocaine euphoria. This study indicates that buprenorphine dose has a significant and substantial impact on opioid use and a significant but less robust impact on cocaine use, with higher doses and longer time on buprenorphine leading to attenuated cocaine use.

Multidimensional hormonal discrimination of paranoid schizophrenic from bipolar manic patients.

The search for biological markers of psychiatric disorders has traditionally involved univariate approaches, usually focusing upon one measure at a time, and to date has been primarily directed towards the assessment of depressive rather than psychotic illnesses. The present study explores a multidimensional psychoendocrine strategy, using a profile of five hormones, including cortisol, epinephrine, norepinephrine, testosterone, and free thyroxine, and is directed at the differentiation of two major psychotic illnesses, bipolar manic disorder and paranoid schizophrenia. When the levels of these hormones were assessed at admission and biweekly during hospitalization, the mean values for all five hormones were found to differ markedly between the two diagnostic groups. There was, however, always a zone of overlap in levels between the two groups when each of the five hormones were viewed individually, so that at best only about 70% of patients were correctly separated by diagnostic group using any single hormone alone. By contrast, multivariate approaches combining mean values of three or more hormones, using either stepwise discriminant analysis or multidimensional scaling, yielded 95% correct classification of the two diagnostic groups. Similar but not quite as great accuracy of classification was achieved with only the initial hormone sample obtained at the time of hospital admission. These preliminary findings provide encouragement for further exploration of multidimensional hormonal strategies in the search for useful biological criteria to assist in the diagnosis of psychiatric disorders.

Chronic disulfiram treatment effects on intranasal cocaine administration: initial results.

BACKGROUND: Simultaneous abuse of cocaine and alcohol is common. Alcohol decreases negative stimulant effects and potentiates "high." Disulfiram (Antabuse) is being studied in outpatient trials as a cocaine pharmacotherapy with the rationale that inability to modulate cocaine effects with alcohol may decrease cocaine use. METHODS: We examined the interaction of disulfiram and cocaine in a randomized, double-blind, placebo-controlled study where subjects were chronically treated with disulfiram and then participated in intranasal cocaine administration studies. RESULTS: Disulfiram 250 mg/day treatment significantly increased plasma cocaine concentrations (p = .013), heart rate (cocaine 1 mg/kg, p = .046), and systolic (cocaine 2 mg/kg p = .003) and diastolic (cocaine 2 mg/kg, p = .022) blood pressure. "High" and "nervous" ratings were nonsignificantly increased. CONCLUSIONS: The combination of "high" with increased anxiety in the context of inability to lessen negative effects with alcohol may be an effective treatment in selected patients. The significant pharmacokinetic interaction must be considered in the decision regarding use of disulfiram.

Guanine nucleotide binding proteins in opioid-dependent patients.

Guanine nucleotide binding (G) protein levels and functioning in the platelets of 19 methadone-maintained patients were compared to age and sex matched, normal controls. We found that in the methadone patients, G alpha s-levels were significantly higher, while the levels of G alpha i 1/2 and pertussis toxin catalyzed [32P]ADP ribosylation were significantly lower compared to control subjects in platelet membranes. We have further found that when all three of these biochemical indicators were combined in a discriminant function analysis, 79% of the methadone patients were correctly classified and 83% of the controls were correctly classified.

The effects of naltrexone maintenance on the response to yohimbine in healthy volunteers.

BACKGROUND: Preclinical research suggests that opiate antagonists may alter stress responsiveness. This study describes the effect of pretreatment with the opioid antagonist naltrexone on the response to a noradrenergic stressor, the alpha-2-receptor-antagonist, yohimbine, in healthy subjects. The current study was designed to compare the change in responses to yohimbine after 2 weeks of treatment with naltrexone to the response after at least 2 weeks of treatment with placebo. METHODS: After a week of placebo naltrexone treatment, ten subjects were randomized into a double-blind cross-over to placebo or active naltrexone (50 mg p.o. daily) on weeks 2 to 4, and the converse condition for weeks 5 to 7. Subjects received challenges in a random, fixed sequence with placebo and active yohimbine (i.v., 0.2 mg/kg) on weeks 1, 4, and 7. The active-active combination generally had the strongest drug effects. RESULTS: There were statistically significant (p < .05) interactions of naltrexone condition X yohimbine condition for subject ratings of "nervous," "not liking the drug effect," "talkative," and "urge to urinate," and a trend (p < .10) for cortisol levels. CONCLUSIONS: The results suggest that clinically used naltrexone doses alter sensitivity to yohimbine.