Ketamine Inhalation Alters Behavior and Lower Urinary Tract Function in Mice.

We aimed to evaluate behavioral and lower urinary tract changes in mice using a novel ketamine inhalation model mimicking human ketamine abusers and compare the results to those obtained using a ketamine intraperitoneal injection model. C57BL/6N mice were placed in a transparent acrylic observation cage connected to an ultrasonic nebulizer producing ketamine (KI) or saline (SI) fog. The mice were given KI or SI fog twice a week for three months. In another experiment arm, the mice were given intraperitoneal ketamine injections (KP) or saline injections (SP) twice a week for three months. The presence of urine ketamine (>100 ng/mL) was determined using a quick test kit. Locomotor activity was recorded by video using the open field test. Lower urinary tract function was assessed using urine spots, cystometry and histology. KI and KP mice crossed the center more frequently and traveled farther than SI and SP mice. Only KI mice, however, demonstrated popcorn-like jumping, and frequent center crossing. Detrusor overactivity, reduced cystometric bladder capacity, and denuded mucosa were observed in both KI and KP mice. Ketamine inhalation induces behavioral and lower urinary tract changes in mice that are comparable to intraperitoneal ketamine injections.

Diversities of behavioral traits and neuropsychological function in different substance addiction.

OBJECTIVE: There are various temperaments and personality characters that modulate the development of substance addiction. The pharmacological properties of substances would alter the homeostasis of brain function and influence the neuropsychological performance through different neurotransmissions which then facilitate diverse emotional and behavioral responses. Our goal is to assess the interaction between personality characteristics, neuropsychological performances and Stroop interference in alcoholics, heroin and amphetamine dependent persons. METHODS: Subjects with alcohol (N=95), heroin (N=82) and amphetamine (N=57) dependence were recruited. Diagnostic interview and questionnaires evaluating the psychiatric symptoms were done, followed by neuropsychological assessments of Stroop and Wisconsin card sorting tests (WCST). Differences between the study groups were analyzed by one-way ANOVA with Scheffe's test. RESULTS: The individuals with alcohol dependence had significantly higher scores of neurotic, dysphoric and impulsive traits (P<0.001) than heroin and amphetamine dependent groups. In Stroop tests, the alcohol dependent subjects also showed delayed response on incongruent naming interferences compared to both of heroin and amphetamine groups (P<0.001). Perseverative errors and responses of WCST were significantly higher in heroin than in alcoholic dependent persons (P<0.01). CONCLUSIONS: Individuals with different substance dependence have distinct behavioral traits for developing addicted behaviors and had variant deficits of neuropsychological function.

Betaine enhances antidepressant-like, but blocks psychotomimetic effects of ketamine in mice.

Ketamine is emerging as a new hope against depression, but ketamine-associated psychotomimetic effects limit its clinical use. An adjunct therapy along with ketamine to alleviate its adverse effects and even potentiate the antidepressant effects might be an alternative strategy. Betaine, a methyl derivative of glycine and a dietary supplement, has been shown to have antidepressant-like effects and to act like a partial agonist at the glycine site of N-methyl-D-aspartate receptors (NMDARs). Accordingly, betaine might have potential to be an adjunct to ketamine treatment for depression. The antidepressant-like effects of ketamine and betaine were evaluated by forced swimming test and novelty suppressed feeding test in mice. Both betaine and ketamine produced antidepressant-like effects. Furthermore, we determined the effects of betaine on ketamine-induced antidepressant-like and psychotomimetic behaviors, motor incoordination, hyperlocomotor activity, and anesthesia. The antidepressant-like responses to betaine combined with ketamine were stronger than their individual effects. In contrast, ketamine-induced impairments in prepulse inhibition, novel object recognition test, social interaction, and rotarod test were remarkably attenuated, whereas ketamine-induced hyperlocomotion and loss of righting reflex were not affected by betaine. These findings revealed that betaine could enhance the antidepressant-like effects, yet block the psychotomimetic effects of ketamine, suggesting that betaine can be considered as an add-on therapy to ketamine for treatment-resistant depression and suitable for the treatment of depressive symptoms in patients with schizophrenia.

Lifestyle modification and behavior therapy effectively reduce body weight and increase serum level of brain-derived neurotrophic factor in obese non-diabetic patients with schizophrenia.

The goal of the study was to elucidate the relationship between serum circulating brain-derived neurotrophic factor (BDNF) and body weight reduction via lifestyle modification and behavior therapy in obese non-diabetic patients with chronic schizophrenia. Thirty-three obese non-diabetic subjects with schizophrenia treated with stable antipsychotic medication in a day-care unit for at least 3 months were recruited. Thirty age-, body weight-matched subjects without psychiatric disorders were enrolled as controls. All participants underwent a 10-week weight reduction program, including lifestyle modification, psychosocial treatment, behavior therapy and exercise in the day-care unit. Blood biochemistry, serum BDNF, adipokine (adiponectin), inflammatory markers (C-reactive protein, tumor necrosis factor-alpha and interleukin-6) and oral glucose tolerance test were evaluated before and after the program. Serum BDNF concentrations were significantly lower among patients with schizophrenia compared to control subjects. Serum BDNF levels were significantly increased following the weight reduction program. Elevations in serum BDNF levels were positively correlated with body weight and body mass index reduction. Altogether, our results demonstrate that a non-pharmacological weight reduction program effectively reduces body weight with significant elevation of serum BDNF levels in obese non-diabetic patients with schizophrenia.

The role of ALDH2 and ADH1B polymorphism in alcohol consumption and stroke in Han Chinese.

The genes encoding the enzymes for metabolising alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) - exhibit genetic polymorphism and ethnic variations. Although the ALDH2*2 variant allele has been widely accepted as protecting against the development of alcoholism in Asians, the association of the ADH1B*2 variant allele with drinking behaviour remains inconclusive. The goal of this study was to determine whether the polymorphic ADH1B and ALDH2 genes are associated with stroke in male Han Chinese with high alcohol consumption. Sixty-five stroke patients with a history of heavy drinking (HDS) and 83 stroke patients without such a history (NHDS) were recruited for analysis of the ADH1B and ALDH2 genotypes from the stroke registry in the Tri-Service General Hospital, Taipei, Taiwan, between January 2000 and December 2001. The allelotypes of ADH1B and ALDH2 were determined using the polymerase chain reaction-restriction fragment length polymorphism method. The HDS patients (3 per cent) showed a significantly lower ALDH2*2 allele frequency than NHDS patients (27 per cent) (p < 0.001). After controlling for age, patients with HDS were associated with a significantly higher occurrence of cigarette smoking (p < 0.01) and liver dysfunction (p < 0.01). Multiple logistic regression analyses revealed that the ALDH2*2 variant allele was an independent variable exhibiting strong protection (odds ratio 0.072; 95 per cent confidence interval 0.02-0.26) against HDS after adjustment for hypertension, diabetes mellitus, smoking status and liver dysfunction. By contrast, allelic variations in ADH1B exerted no significant effect on HDS. The present study indicated that, unlike ALDH2*2, ADH1B*2 appears not to be a significant negative risk factor for high alcohol consumption in male Han Chinese with stroke.

Potentiating effect of fluphenazine decanoate and risperidone on development of neuroleptic malignant syndrome.

We present the case of a woman with paranoid schizophrenia who was receiving oral risperidone. She developed neuroleptic malignant syndrome (NMS) following the addition of depot fluphenazine for the treatment of refractory delusions. NMS subsided and psychotic features were controlled after both antipsychotics were discontinued and the patient was treated instead with olanzapine.

Brain-derived neurotrophic factor, adiponectin, and proinflammatory markers in various subtypes of depression in young men.

OBJECTIVES: We aimed to investigate levels of brain-derived neurotrophic factor (BDNF), adiponectin, and proinflammatory cytokines in various subtypes of depression in a cohort of young men. METHODS: Sixty-two men 18-30 years of age were recruited for the study. Forty-two were newly diagnosed with depression according to DSM-IV criteria and were divided into three subtypes: reactive depression (N = 13), major depression (N = 18), and bipolar depression (N = 10). Controls included 21 young men without significant clinical morbidity. Serum levels of BDNF, adiponectin, high sensitivity C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were measured. RESULTS: Serum BDNF was significantly lower and TNF-alpha significantly higher than controls for all subtypes of depression. No statistically significant differences between subtypes were found for BDNF, adiponectin, hsCRP, TNF-alpha, or IL-6. Although established diagnosis of depression and level of TNF-alpha were found to independently affect BDNF level in depressed subjects, they executed inverse effects. No associations were found between BDNF and adiponectin, hsCRP, TNF-alpha, or IL-6 in any depressed subject, showing that decreased BDNF in depression is influenced by multiple factors and complex mechanisms, including environmental and genetic concerns. No influence of age on BDNF level was found in any depressive subtype. CONCLUSIONS: Our results lend support to the cytokine and neurotrophic hypotheses of depression by demonstrating significantly lower levels of BDNF in all subtypes of depression. The mechanism underlying this phenomenon is uncertain and assumed to be multifactorial. Development of novel antidepressant treatments will require a multidisciplinary approach.

Antidepressant effects on insulin sensitivity and proinflammatory cytokines in the depressed males.

Growing evidence suggests that mood disorder is associated with insulin resistance and inflammation. Thus the effects of antidepressants on insulin sensitivity and proinflammatory responses will be a crucial issue for depression treatment. In this study, we enrolled 43 non-diabetic young depressed males and adapted standard testing procedures to assess glucose metabolism during 4-week hospitalization. Before and after the 4-week antidepressant treatment, participants underwent oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity (S(I)), glucose effectiveness (S(G)), acute insulin response, and disposition index (DI) were estimated using the minimal model method. The plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and adiponectin were measured. The Hamilton depression rating scale (HAM-D) total scores were reduced significantly during the course of treatment. There were no significant changes in the parameters of S(I), S(G), and DI. Compared to drug naïve status, the level of plasma IL-6 was significantly elevated (0.77 to 1.30 pg/ml; P = .001) after antidepressant therapy. However, the concentrations of CRP, TNF-alpha, and adiponectin showed no differences during the course of treatment. The results suggest that antidepressants may promote stimulatory effect on the IL-6 production in the early stage of antidepressant treatment.

Insulin sensitivity, proinflammatory markers and adiponectin in young males with different subtypes of depressive disorder.

OBJECTIVE: This study was designed to evaluate insulin sensitivity, proinflammatory markers and adiponectin concentration in young males with different subtypes of depressive disorder. METHODS: Nonobese young males with depressive disorder (ages between 18 years and 30 years; body mass index, BMI < or = 25 kg/m(2)) were recruited and divided into reactive depression (RD, N = 14), major depression (MD, N = 21) and bipolar depression (BD, N = 15) based on clinical course and symptom changes in Hamilton rating scale for depression (HAM-D). Fourteen age- and BMI-matched healthy males were enrolled as controls. All of the participants received a 75-g oral glucose tolerance test (OGTT). Insulin sensitivity and beta-cell function were calculated by minimal model method from the frequently sampled intravenous glucose tolerance test. Plasma C-reactive protein (CRP), adiponectin, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were determined. RESULTS: Compared to the controls, insulin sensitivity (S(I)) were significantly lower in MD and BD (0.78 +/- 0.09 min(-1)/pmol and 0.75 +/- 0.09 min(-1)/pmol vs. 1.09 +/- 0.08 x 10(-5) min(-1)/pmol, P < 0.05, respectively). Acute insulin response (AIR) to intravenous glucose was elevated in BD as compared to control and RD groups (6079.9 +/- 841.8 pmol vs. 3339.8 +/- 356.4 pmol and 3494.8 +/- 337.7 pmol, P < 0.05, respectively). Plasma adiponectin level was diminished in BD group as compared to the control and RD groups (7.41 +/- 0.45 microg/ml vs. 9.07 +/- 0.54 microg/ml and 9.38 +/- 0.46 microg/ml; P < 0.05 and P < 0.01, respectively). By regression analysis, a significantly negative correlation between HAM-D score and S(I) was found in MD (r = -0.60, P = 0.005) and BD groups (r = -0.57, P = 0.04). CONCLUSIONS: The results suggest that there is an inverse relationship between both major and bipolar depression and insulin resistance in nonobese young males.