Administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats

RATIONALE: Ghrelin is a peptide of 28 amino acids found in mammals that increases the release of growth hormone, food intake, and body weight. OBJECTIVES: We investigated the relationship between ghrelin and the states of anxiety and depression by giving rats either antisense DNA for ghrelin, scrambled DNA or vehicle into the lateral ventricle of rats. RESULTS: In forced swimming tests, rats that received antisense DNA decreased the length of time that they were immobile in the water. Ghrelin antisense oligonucleotides produced an anxiolytic-like effects in the elevated plus maze test, black and white test, or conditioned fear tests. Treatment with antisense DNA for ghrelin significantly decreased rat body weight. No significant effect on general locomotor activity was seen. CONCLUSIONS: These results suggest that administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats.     

Genome-wide association studies of antidepressant outcome: a brief review

Genome-wide association studies (GWAS) of antidepressant treatment outcome have been at the forefront of psychiatric pharmacogenetics. Such studies may ultimately help match medications with patients, maximizing efficacy while minimizing adverse effects. The hypothesis-free approach of the GWAS has the advantage of interrogating genes that otherwise would have not been considered as candidates due to our limited understanding of their function, and may also uncover important regulatory variation within the large regions of the genome that do not contain protein-coding genes. Three independent samples have so far been studied using a genome-wide approach: The Sequenced Treatment Alternatives to Relieve Depression sample (STAR*D) (n = 1953), the Munich Antidepressant Response Signature (MARS) sample (n = 339) and the Genome-based Therapeutic Drugs for Depression (GENDEP) sample (n = 706). None of the studies reported results that achieved genome-wide significance, suggesting that larger samples and better outcome measures will be needed. This review discusses the published GWAS studies, their strengths, limitations, and possible future directions.     

Hypericum perforatum differentially affects corticosteroid receptor-mRNA expression in human monocytic U-937 cells

A dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis represents a prominent finding in major depression, possibly related to a dysfunction of the corticosteroid receptor system. Antidepressants are involved in the restoration of the altered feed-back mechanism of the HPA-axis, probably via normalization of corticosteroid receptor functions. Since Hypericum perforatum has antidepressive properties, we here examined its putative actions on glucocorticosteroid receptor mRNA levels in human blood cells as a peripheral model for neuroendocrine effects in human brain cells.Our data show that Hypericum (LI 160) affects the cellular mRNA levels of both, the glucocorticoid receptor (GR)-α and its inhibitory counterpart, the GR-β, at clinically-relevant concentrations. Under these conditions, a bimodal effect was observed. Dose-response studies suggest a rather small effective concentration range and time-effect data show a primary and transient up-regulation of GR-α mRNA levels and a down-regulation of GR-β mRNA levels after 16 h of treatment. The sodium channel blocker benzamil neutralized the effects of Hypericum, pointing to an at least partial mechanism of action via this pathway.In conclusion, Hypericum treatment differentially affects GR-mRNA levels in the human system. Our data suggest a bimodal effect on GR, resulting in a time-and dose-related modification of GR-mediated cellular effects. Such a mechanism has been alleged as an important way of action for a number of antidepressants. It is the first time that a specific effect on both receptors, especially on the subtype of GR-β, is shown under antidepressive treatment in a human system under in vitro conditions.     

重庆地区20家医院2006～2008年抗抑郁药利用分析

目的:评价重庆地区医院抗抑郁药的应用情况和发展趋势。方法:采用回顾性方法,对重庆地区20家医院2006～2008年抗抑郁药的销售金额、用药频度、日均费用等数据进行统计、分析。结果:各年度抗抑郁药销售金额呈逐年上升趋势,销售金额排序前3位的分别是帕罗西汀、氟西汀、米氮平,用药频度排序列前3位的分别是氟西汀、氟哌噻吨/美利曲辛、帕罗西汀。结论:选择性5-羟色胺再摄取抑制剂类抗抑郁药的应用占主导地位,新型抗抑郁药应用前景广阔。     

Evidence for the involvement of the noradrenergic system, dopaminergic and imidazoline receptors in the antidepressant-like effect of tramadol in mice

The involvement of the noradrenergic system, imidazoline, dopaminergic and adenosinergic receptors in the antidepressant-like action of tramadol in the mouse forced swimming test (FST) was evaluated in this study. The antidepressant-like effect of tramadol (40 mg/kg, per oral, p.o.) in the FST was blocked with yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), α-methyl-para-tyrosine methyl ester (AMPT, 100 mg/kg, i.p., an inhibitor of tyrosine hydroxylase), efaroxan (1 mg/kg, i.p., an imidazoline I₁/α₂-adrenoceptor antagonist), idazoxan (0.06 mg/kg, i.p., an imidazoline I₂/α₂-adrenoceptor antagonist), antazoline (5 mg/kg, i.p., a ligand with high affinity for the I₂ receptor), haloperidol (0.2 mg/kg, i.p., a non selective dopamine receptor antagonist), SCH23390 (0.05 mg/kg, subcutaneously, s.c., a dopamine D₁ receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D₂ and D₃ receptor antagonist) but was not reversed by prazosin (1 mg/kg, intraperitoneally, i.p., an α₁-adrenoceptor antagonist) and caffeine (3 mg/kg, i.p., a nonselective adenosine receptor antagonist). Monoamine oxidase-A and -B (MAO-A and MAO-B) activities were neither inhibited in the whole brain nor in specific brain regions of mice treated with tramadol. These data demonstrated that the antidepressant-like effect caused by oral administration of tramadol in the mouse FST is mediated by the noradrenergic system, dopaminergic and imidazoline receptors.     

A Gas Chromatographic Method for the Determination of Antidepressant Drugs in Human Serum

Abstract: A universal gas chromatographic method for the determination of the most commonly used antidepressant drugs in I ml of serum is described. Prior to extraction the samples were washed with hexane at acid pH. After the hexane wash the drugs were extracted into hexane at pH approximately 10, and subsequently reextracted from the hexane into a 1% solution of formic acid in methanol. The methanolic phase was evaporated, the residue dissolved in isopropanol and analysed by gas chromatography with nitrogen detection on a 3% OV-225 column. Recoveries for amitriptyline, nortriptyline, clomipramine, desmethylclomipramine, doxepin, desmethyldoxepin, imipramine, desipramine, maprotiline, protriptyline, trimipramine and desmethyl-trimipramine were found to be 80% or higher. Limits of detection were found to be 5–10 ng/ml for tertiary amines and 10–20 ng/ml for secondary amines. Interferences from some common basic drugs were investigated as well as interferences between different antidepressant drugs. Gas chromatographic data are given for 28 drugs and metabolites.     

Effects of adrenergic blockers on the inhibition of muricide by desipramine and noradrenaline injected into the amygdala in olfactory bulbectomized rats

Muricide in olfactory bulbectomized rats (OB rats) is readily inhibited by systemic administration of desipramine (DMI) or microinjection of DMI and noradrenaline (NA) into the medial amygdaloid nucleus. The present experiment investigated whether the muricide inhibition produced by these forms of drug treatment was mediated by alpha- or beta-noradrenergic receptors in the central nervous system. Muricide inhibition produced by systemic administration of DMI was antagonized by an alpha-blocker phenoxybenzamine but unaffected by a beta-blocker sotalol, although administration of these adrenergic blockers alone had no effect on muricide. Muricide inhibition induced by the microinjection of DMI and NA into the medial amygdaloid nucleus was similarly antagonized by pretreatment of phenoxybenzamine injected into the same site, but sotalol had no effect. Injection of phenoxybenzamine or sotalol alone into the medial amygdaloid nucleus did not elicit any changes in muricide. These findings suggest that mechanisms mediated by brain noradrenergic alpha-receptor play an important role in muricide inhibition by tricyclic antidepressants in rats and that the medial amygdaloid nucleus is an important site of action of these drugs.     

Assessment of symptom change from improvement curves on the Hamilton depression scale in trials with antidepressants

A total of 97 patients, who participated in two studies on the relationship between the clinical effect and plasma levels of imipramine and clomipramine, were examined for improvement curves by use of weekly ratings on the Hamilton Depression Scale (HDS). Although we confirmed that our six-item HDS subscale, in contrast to the total 17-item HDS, was a one-dimensional measure of depression, the Rasch analysis showed that the weekly improvement in subscale scores only applied to the individual patient, i.e. an average improvement curve for a group of depressed patients is an abstraction to which the individual curves cannot be transferred. Our results indicate, however, that when the subscale scores are transformed into three clinical categories of depression: no, mild (minor), moderate/-severe (major) they could be described by a common improvement curve for all patients. This is illustrated by the percentage of patients who, week to week, changed from major to minor or no depression, or from minor to no depression. We found no specific improvement pattern for imipramine or clomipramine which could be used diagnostically. There is reason to assume that patients completing a controlled trial necessarily will follow a monotonic improvement curve, and the improvement pattern of all patients fulfilling the entry criteria should, therefore, always be reported. The present study thus indicates that calculation of average improvement curves is neither clinically nor statistically meaningful, and should be replaced by measures of changes in number of patients in different main severity categories, or by the final rating score. No difference in outcome between imipramine and clomipramine was shown neither on the subscale nor on the 17-item HDS.     

The effect of mepiprazole on central monoamine neurons. Evidence for increased 5-hydroxytryptamine and dopamine receptor activity

In combined biochemical, histochemical and functional studies on central monoamine neurons it has been shown that a pyrozolyl derivative with a phenyl piperazine side-chain (PAP) exerts marked effects on central dopamine (DA) and particularly 5-hydroxytryptamine (5-HT) neurons. The brain 5-HT turnover was reduced with doses down to 0.25 mg/kg, and spontaneous overflow of radioactivity from ³H-5-HT-labelled cortical slices was markedly increased by PAP in a concentration of 10^?6 M. PAP may therefore cause extragranular release of 5-HT stores, since the 5-HT levels were not affected. In agreement with this view, sexual behaviour in the female rat, which is controlled by an inhibitory 5-HT pathway, was inhibited by low doses (0.1–0.5 mg/kg) of PAP. The extensor hindlimb reflex, which is dependent of 5-HT receptor activity, was only increased with higher doses (2.5–10 mg/kg), suggesting that the spinal 5-HT nerve terminals are less sensitive to the releasing action of PAP. A certain direct activation of spinal 5-HT receptors may also be involved, since the actions of PAP in the spinal cord were independent of presynaptic 5-HT stores. The actions of PAP on the DA neurons mainly involve a presynaptic action in the DA nerve terminals leading to increased DA receptor activity. This action may primarily involve a blockade of DA uptake (50% inhibition at 10^?6 M) and/or an extragranular release of DA (two-fold increase in spontaneous overflow at 10^?6 M). The DA turnover was not clearly affected, although a trend to a reduction was observed especially in the nuc. accumbens, probably as a result of a compensatory nervous feedback reducing nervous impulse flow. In agreement with the view mentioned above, PAP mimics amphetamine and not apomorphine in the rotometer model which reveals changes in DA receptor activity. PAP in doses of 0.5–1 mg/kg causes a turning towards the denervated side. The brain noradrenaline (NA) turnover is only significantly increased with somewhat higher doses (5–10 mg/kg) and may be related ot NA receptor blockade, since the L-DOPA-induced increase in flexor activity is blocked by PAP in doses down to 0.5 mg/kg.It is suggested that the extragranular release of 5-HT caused by PAP is partly responsible for the inhibition of conditioned avoidance behaviour and the reduction of threatening behaviour found after PAP in low doses (0.05–0.5 mg/kg). In the clinic, PAP may prove to be a new therapeutic tool in the treatment of depressions due to 5-HT deficiency. Its actions on DA terminals may also prove helpful in this respect. When combined with L-DOPA, PAP may also help to alleviate the motor deficits in parkinsonian patients with a moderate degree of degeneration of the DA system in view of its action on DA uptake and/or release.