Efficacy of dupilumab in chronic prurigo and chronic idiopathic pruritus: a systematic review of current evidence and analysis of response predictors.

Dupilumab has demonstrated a great reduction in chronic pruritus that is the hallmark of atopic dermatitis (AD). Underscoring relevant pathogenesis similarities emerging from AD, chronic idiopathic pruritus (CIP) and chronic prurigo (CP), several authors suggested the beneficial role of dupilumab in these conditions. The evidence on this subject is limited with no precise data available. In this study, we carried out a systematic literature review in order to evaluate the efficacy of dupilumab on both pruritus and skin manifestations in the two largest retrospective cohorts of patients with CP and CIP and tried to identify potential response predictors. Electronic searches were conducted on 4 databases. Our primary outcome was the improvement in pruritus measured by a reduction in the patient's reported numerical rating scale of itch (NRSI) by >4. Secondary outcomes included the proportion of patients with a complete response at the end of treatment, reduction in the number of lesions by the Investigator Global Assessment (IGA), improvement in numerical rating scale of sleep (NRSS), improvement in quality of life measured by the Dermatology Life Quality Index (DLQI), time until patient perceived any improvement (Time-First) and time until the patient-reported absence of pruritus (Time-Final). Descriptive statistics were calculated for each demographic and clinical variable. Univariate logistic regression analyses were conducted to explore the association between response to dupilumab and potential predictive factors. We included 25 articles in the analysis, counting a total of 153 patients. Based on CP patients' cohort (n = 132), the mean NRSI at baseline was 8.79 ± 0.86 and the NRSI final was 2.32 ± 1.27. The mean time to first improvement was 5.18 ± 3.13 weeks, while the time to complete improvement of pruritus (Time-final) was 13.6 ± 12.0 weeks. Ninety patients out of 109 (83%) noticed an improvement in pruritus before 4 weeks of dupilumab therapy. At the end of treatment, 18 patients out of 126 (14%) had a complete remission of pruritus and 110 patients out of 123 (89%) had a reduction of NRSI >4. The reduction in NRSI was significantly greater in patients improving before 4 weeks of treatment (6.57 ± 1.71) compared with patients improving in more than 4 weeks (5.49 ± 1.39, P < 0.001). Patients with history of AD and those who have been previously treated with cyclosporine or methotrexate had a significantly lower reduction in NRSI (e.g. 6.05 ± 1.34 vs. 7.08 ± 1.90, P < 0.01 for nonassociated AD patients). Based on CIP patient's cohort (n = 21), the mean NRSI at baseline was 8.33 ± 0.80 and the NRSI final was 0.95 ± 0.59. The mean time to first improvement was 2 ± 0 weeks, while the time to complete improvement (Time-final) was 14.6 ± 10 weeks. At the end of treatment, 3 patients out of 21 (14%) had a complete remission of pruritus and 100% of patients had a reduction of NRSI >4. No serious treatment-emergent adverse events were reported. The most common adverse event was mild conjunctivitis (13 cases). We highlight the importance of one early sign of improvement as a predictor of the future response to dupilumab: the improvement before 4 weeks of treatment that leads significantly to a greater final reduction in NRSI. Furthermore, patients with the presence or history of atopy appear to be less responsive to dupilumab than nonatopic patients and develop more side effects, in particular conjunctivitis.

[Cutaneous metastases on the extremities]. / Métastases cutanées des extrémités.

BACKGROUND: Cutaneous metastases (CM) on the extremities are rare complication of cancer with poor prognosis. In general, lesions simulate an infection. Herein, we report two new cases with atypical presentation. PATIENTS AND METHODS: Case no 1: a 71-year-old man consulted for suspicion of left hand pyogenic granuloma present for 3 months. His history revealed two treated squamous-cell carcinomas (tongue and lung). On physical examination, he presented three budding and foul-smelling lesions on his left hand. Histopathology showed metastasis of squamous-cell carcinoma. Radiographic examination revealed spread of pulmonary nodules with suspicion of metastasis. Case no 2: a 68-year-old man was hospitalized for indurated edema of the right leg present for several months. Six months earlier, he had undergone surgery for left pulmonary adenocarcinoma without metastasis. Physical examination revealed an indurated edema on the right foot. Histopathology showed metastasis from adenocarcinoma. A scan revealed several osteolytic lesions in the right foot as well as lymphadenopathy. DISCUSSION: Herein, we report two original cases of CM of the extremities diagnosed as tumor progression. This is a rare complication of variable clinical presentation and impacts both cancer management and prognosis. It is important to consider the diagnosis when distal cutaneous lesions persist, particularly where there is a history of cancer.

Sex- and tissue-specific expression of "similar to nothepsin" and cathepsin D in relation to egg yolk formation in Gallus gallus.

Egg yolk constitutes the main storage compartment of the avian egg and the first nutritional source that supports embryonic growth. Most egg yolk components are synthesized by the liver of laying hens at sexual maturity and are secreted into the blood to be further transferred into the ovarian oocyte (yolky follicle) by receptor-mediated endocytosis. Egg yolk proteins are secreted as precursors and must undergo proteolytic processing to be bioactive. It is assumed that chicken cathepsin D, an aspartic protease, is a key enzyme in this process. Very recently, a novel aspartic protease, namely "similar to nothepsin," has been identified in the egg yolk. Previous experiments conducted in Antarctic fish have shown that the expression of nothepsin is tissue- and sex-specific. To gain insight into the specificities of expression of both cathepsin D and "similar to nothepsin" in Gallus gallus, we compared their distribution in various tissues, in male and females. Cathepsin D is ubiquitously expressed in all tissues examined, including liver of both male and female adults, and its expression is stable during sexual maturation. In contrast, "similar to nothepsin" expression is unique to the liver of adult females and is sex steroid-dependent as it increases gradually in the liver of hens during sexual maturation. The sexual dimorphic expression of the "similar to nothepsin" gene suggests that the activity of this protein is regulated by the steroid environment of laying hens and is specifically adapted for inclusion in the yolk. Further studies are needed to assess whether "similar to nothepsin" assists cathepsin D in the proteolytic processing of egg yolk proteins during follicular growth.

[The problems with the use of benzodiazepines in elderly patients]. / Les problèmes posés par l'utilisation des benzodiazépines chez le patient âgé

Benzodiazepines (BZD) are widely used to treat anxiety and insomnia in elderly patients. The interest of this prescription is discussed in this article. The discussion is based on the pharmacological properties and adverse effects of BZDs in the elderly. The conclusions are that BZDs should be rarely prescribed in this population; many patients treated by BZDs should be withdrawn and therapeutic strategies, other than BZDs, should be considered to treat anxiety and insomnia in these patients. Problems posed by BZD in the aged patient are both of a pharmacodynamic and pharmacokinetic order. In comparison to young adult users, BZD users among the aged are essentially women; the latter take these medications during important periods in their lives and often have a strong comorbidity, such as cardiovascular or rhumatological problems or even psychiatric problems, such as depression or panic disorders. Aged patients who take BZD at high doses can also consume other drugs, such as alcohol, and often have a psychiatric history. Some important side effects are associated with the use of BZD; essentially concerning falls, and it has been noticed for some years that problems posed by aged car drivers can be enhanced by BZD. It is difficult to know if continual users of BZD really have an advantage over other users. However, instruments, such as an indicator in the form of an algorithm, have been developed to identify the appropriateness of prescribing BZD to elderly patients. It is obvious that it is essential, whenever possible, to have a recourse strategy for cessation, and as much as possible to use BZD with a short half-life that are not oxidised, i.e. essentially BZD that are not metabolised in the strictest sense of the term, such as lorazepam or temazepam. Daily doses must be extremely limited and duration of use should not exceed two or three months in young patients.

Factors triggering abolishment of benzodiazepines effects in the Four-Plate Test--retest in mice.

Abolishment of anxiolytic-like effects of diazepam occurs during re-exposure to some animal tests of anxiety. We investigated the loss of anxiolytic-like effects of diazepam during Trial 2 on previously undrugged mice, namely one-trial tolerance (OTT). Swiss mice were subjected to 1) Four-Plate Test (FPT) without punishments in Trial 1 or 2) FPT without punishments in both Trials or 3) FPT with spatial modifications in Trial 1 or 4) Elevated Plus Maze (EPM), then 24 h later to FPT, with saline, diazepam (1 mg/kg) or DOI (1 mg/kg). Removing punishments in Trial 1 does not counteract the effect reduction of diazepam in Trial 2, but spatial modifications of the aversive environment. Previous exposure to EPM does not trigger a loss of efficacy of diazepam in FPT. Electric punishments do not trigger OTT to benzodiazepines; whilst knowledge of the environment seems to be responsible for this phenomenon. FPT may be useful to study OTT because punishments potentate OTT in this model of anxiety.

Effect of antidepressant drugs on 6-OHDA-treated mice in the FST.

There is growing evidence suggesting that dopamine could be indirectly involved in the appearance of behavioural effects of antidepressants. In this study, we induced a partial (over 70%) and non-reversible depletion of dopamine-containing neurons in mice by i.c.v. infusion of 6-OHDA. Then, we compared the antidepressant-like effect of drugs (citalopram, paroxetine, desipramine and imipramine) with or without dopamine depletion in the mice forced swimming test. Our results clearly show that lesion with 6-OHDA does not modify the response of mice to desipramine and imipramine, whereas dopamine depletion abolished the antidepressant-like effect of citalopram and paroxetine. It could then be suggested that antidepressant-like effect of selective serotonin reuptake inhibitors (paroxetine and citalopram) in the mice FST requires the activation of dopaminergic pathways to occur.

[Sleep and wakefulness drugs and their indications]. / Les médicaments du sommeil et de la vigilance et leurs indications.

This paper is a review of the use of drugs in sleep and wakefulness disorders. Insomnia is more often a symptom than an autonomic disorder. Good knowledge of the clinical facts is required before prescribing hypnotics. Sedative drugs are potentially hypnotics; yet, melatonin is not sedative and may be considered to resynchronise of sleep phases. Stimulant drugs are prescribed in attention disorders; methylphenidate is the more frequently used. Narcolepsy, which is characterized by daytime sleepiness and irresistible episodes of sleep, is treated by an alpha1 noradrenergic stimulant modafinil which has no amphetaminic properties.

Combined effect of divergent selection for breast muscle ultimate pH and dietary amino acids on chicken performance, physical activity and meat quality.

Responses to changes in dietary Lys and other essential amino acid (AA) concentrations were evaluated in 480 male and female broilers originating from two lines divergently selected for high (pHu+) or low (pHu-) ultimate pH (pHu) of breast muscle. The two genetic lines were fed with two grower isoenergetic diets differing in both true digestible Lys (control=10.2 g/kg and experimental=7.0 g/kg) and amounts of other essential AA calculated in relation to Lys, which were sufficient for the control diet or in excess for the experimental diet. There were six repetitions per treatment. Birds were weighed individually at days 0, 21, 28 and 43. Feed consumption was recorded per pen and feed conversion was calculated over the growing period. The physical activity and walking ability of broilers were recorded during the whole rearing period. Breast and leg yield, and abdominal fat percentage were measured at 43 days of age, as were pHu, color, drip and cooking loss, Warner-Bratzler shear force, and curing-cooking yield of the breast Pectoralis major and pHu of the thigh Sartorius muscle. Divergent selection greatly affected most breast meat quality traits without significantly changing growth rate or feed efficiency. When subjected to a variation in dietary intake of AA, birds from the two genotypes responded in a similar way in terms of animal's growth, feed efficiency, body composition and meat quality traits. Although line and diet did not affect physical or feeding activities of the broilers, a significant effect of line-by-diet interaction was observed on gait score. Contrary to the pHu- birds, the walking ability of pHu+ birds was impaired when fed the control diet that favored growth and breast muscle development and limited storage of carbohydrate in muscle.

Antidepressant-like activity of selective serotonin reuptake inhibitors combined with a NK1 receptor antagonist in the mouse forced swimming test.

Substance P antagonists of the neurokinin-1 receptor type (NK1) have growing interest as new antidepressant therapies. It has been postulated that these drugs exert this putative therapeutic effect without direct interactions with serotonin (5-HT) neurons. In line with this assumption, previous intracerebral in vivo microdialysis experiments provided evidence that the NK1 receptor antagonists did not change basal cortical 5-HT levels. However, we found that increases in cortical 5-HT overflow caused by systemic injection of the selective serotonin reuptake inhibitor (SSRI), paroxetine was higher in freely moving (C57BL/6x129sv) NK1-/- mutants than in wild-type NK1+/+ mice. More recently, a pharmacological study has led to a similar conclusion since GR205171, a NK1 receptor antagonist, potentiated paroxetine-induced increases in cortical 5-HT dialysate following its acute systemic or intra-raphe administration to wild-type mice . In the present study, we tested whether an acute combination of SSRI and NK1 receptor antagonist could display antidepressant-like activity using the forced swimming test in Swiss mice. We found that a single systemic dose of GR205171 (10 and 30 mg/kg, i.p.) had no effect by itself. However, it selectively potentiated the antidepressant-like activity of subactive doses of two serotonergic antidepressant drugs, citalopram and paroxetine (without psychomotor stimulant activity), but not that of noradrenaline reuptake inhibitor, desipramine. In agreement with neurochemical data, the present study confirms that co-administration of a NK1 receptor antagonist with an antidepressant drug such as a SSRI may have a therapeutic potential to improve the treatment of major depressive episodes in human compared to SSRI alone.

5-HT2C receptors in psychiatric disorders: A review.

5-HT2Rs have a different genomic organization from other 5-HT2Rs. 5HT2CR undergoes post-transcriptional pre-mRNA editing generating diversity among RNA transcripts. Selective post-transcriptional editing could be involved in the pathophysiology of psychiatric disorders through impairment in G-protein interactions. Moreover, it may influence the therapeutic response to agents such as atypical antipsychotic drugs. Additionally, 5-HT2CR exhibits alternative splicing. Central serotonergic and dopaminergic systems interact to modulate normal and abnormal behaviors. Thus, 5HT2CR plays a crucial role in psychiatric disorders. 5HT2CR could be a relevant pharmacological target in the treatment of neuropsychiatric disorders. The development of drugs that specifically target 5-HT2C receptors will allow for better understanding of their involvement in the pathophysiology of psychiatric disorders including schizophrenia, anxiety, and depression. Among therapeutic means currently available, most drugs used to treat highly morbid psychiatric diseases interact at least partly with 5-HT2CRs. Pharmacologically, 5HT2CRs, have the ability to generate differentially distinct response signal transduction pathways depending on the type of 5HT2CR agonist. Although this receptor property has been clearly demonstrated, in vitro, the eventual beneficial impact of this property opens new perspectives in the development of agonists that could activate signal transduction pathways leading to better therapeutic efficiency with fewer adverse effects.

Tumor necrosis factor alpha and glutathione interplay in chronic heart failure.

The pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), in concert with neurohormones, contributes to chronic heart failure (CHF) progression. This implies that TNF a antagonism may constitute an important target for CHF therapy. However, clinical trials in CHF patients using compounds that trap TNF alpha, comprising infliximab, an antibody directed to TNF alpha, and etanercept, a soluble recombinant receptor of TNF alpha, gave disappointing results bringing back to light the dual, short-term beneficial and long-term harmful effect of TNF alpha. This review focuses on the dual, concentration- and time-related effects of TNF alpha, the yin and yang action of TNF alpha in cardiac ischemia/reperfusion and contraction. Importantly, the harmful effects of TNF a are related to glutathione deficiency, a common hallmark to several other chronic inflammatory diseases. Recently, in rat models of CHF, oral administration of the glutathione precursor, N-acetylcysteine (NAC), was shown to hinder pathways of TNF alpha harmful signalling and to rescue cardiac structure and function. These results suggest that glutathione deficiency in association with TNF alpha activation may play a role in the pathophysiology of CHF and that NAC may represent a potential therapy in CHF.

Decreased type VI adenylyl cyclase mRNA concentration and Mg(2+)-dependent adenylyl cyclase activities and unchanged type V adenylyl cyclase mRNA concentration and Mn(2+)-dependent adenylyl cyclase activities in the left ventricle of rats with myocardial infarction and longstanding heart failure.

OBJECTIVE: To address the effect of longstanding left ventricular (LV) hypertrophy and failure on LV adenylyl cyclase (AC) gene expression, mRNA concentrations of the main cardiac AC isoforms were measured in the non-infarcted area of LV from rats with myocardial infarction (MI), without (H) or with (F) LV failure, and in control (C) rats. Basal, GTP- and forskolin-stimulated Mg(2+)- and Mn(2+)-dependent AC activities were also measured in F and C rats. METHODS: Two- and six months after MI, steady-state AC mRNA concentrations were assessed by Northern blot analysis and RNase protection assay with isoform-specific cDNA and cRNA probes, respectively. AC activities were assessed on LV microsomal fractions using standard procedures. RESULTS: Types V and VI, and types IV and VII were the major and minor AC mRNA isoforms in both the LVs of F and C rats. Two months after MI, no difference in LV type V or VI mRNA to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA ratios was observed in rats with H or F compared to C. Six months after MI, no difference in LV type V mRNA concentration was observed between the three rat groups, whether this level was normalized to GAPDH, poly-(A+) or 18S RNAs. In contrast, a 35% decrease in the type VI mRNA to poly-(A+) RNA ratio and a 29% decrease in the type VI mRNA to 18S RNA ratio was observed only in rats with F compared to C (p < 0.05 vs. C for the two comparisons). Two- and six months after MI, basal and forskolin-stimulated Mg(2+)-dependent AC activities were decreased by 30-35% in F rats compared to C (p < 0.05), whereas Mn(2+)-dependent activities were unchanged. CONCLUSION: Longstanding LV hypertrophy and failure resulting from MI in rats is not associated with altered expression of the most abundant, type V, AC mRNA isoform, whereas that of type VI is decreased. The lack of change in Mn(2+)-dependent AC activities in the LV of F rats suggests that this decrease has no functional consequence on overall AC activity and that decreased Mg(2+)-dependent activities are related to alterations occurring upstream.

3,4-Methylenedioxy analogues of amphetamine: defining the risks to humans.

The 3,4-methylenedioxy analogues of amphetamine [MDMA ("Ecstasy", "Adam"), MDA ("Love") and MDE ("Eve")] are recreational drugs that produce feelings of euphoria and energy and a desire to socialize, which go far to explain their current popularity as "rave drugs". In addition to these positive effects, the drugs are relatively inexpensive to purchase and have the reputation of being safe compared to other recreational drugs. Yet there is mounting evidence that these drugs do not deserve this reputation of being safe. This review examines the relevant human and animal literature to delineate the possible risks MDMA, MDA and MDE engender with oral consumption in humans. Following a summary of the behavioral and cognitive effects of MDMA, MDA and MDE, risks will be discussed in terms of toxicity, psychopathology, neurotoxicity, abuse potential and the potential for drug-drug interactions associated with acute and chronic use.

Replication of action of cholecystokinin tetrapeptide in panic disorder: clinical and behavioral findings.

Eleven patients with panic disorder were challenged with cholecystokinin tetrapeptide (CCK-4) on two occasions. The effects of CCK-4 were consistent except symptom onset was more rapid with the second injection. Demonstrating that the effects of CCK-4 are reproducible in panic patients opens the doors for studies of the effects of drug treatment on CCK-4-induced panic.

Effects of cholecystokinin tetrapeptide on respiratory function in healthy volunteers.

OBJECTIVE: The authors evaluated respiratory response to cholecystokinin tetrapeptide (CCK-4) in healthy volunteers. METHOD: Subjects were randomly assigned to either a CCK-4 (N = 15) or placebo (N = 15) challenge under double-blind conditions. RESULTS: Dyspnea was reported by all of the subjects who received CCK-4 but only one subject who received placebo. CCK-4 caused a significant increase in tidal volume and minute ventilation but had no effect on breathing frequency. Placebo had no effect on any of the respiratory measures. CONCLUSIONS: These data indicate that the behavioral effects of CCK-4 are accompanied by changes in respiration in healthy volunteers.

Evidence for potentiation by CCK antagonists of the effect of cholecystokinin octapeptide in the elevated plus-maze.

Systemic treatment with cholecystokinin octapeptide (CCK-8, 2.5-10 micrograms/kg, s.c.), a non-selective CCK agonist, decreased the exploratory activity of mice in an elevated plus-maze. At higher doses (5-10 micrograms/kg) CCK-8 reduced the frequency of rearing, but only 10 micrograms/kg of CCK-8 significantly inhibited the number of line crossings in the open-field test. A preferential CCKB antagonist L-365,260 (1 and 100 micrograms/kg, i.p.) and a non-selective CCK antagonist proglumide (0.1-1 microgram/kg, i.p.) potentiated the anti-exploratory effect of CCK-8 (2.5 micrograms/kg). Devazepide, a preferential CCKA antagonist, only at a high dose (100 micrograms/kg) tended to increase the action of CCK-8 in the plus-maze. However, the concomitant treatment of CCK-8 with L-365,260 and proglumide, differently from devazepide, also suppressed the locomotor activity in the open-field test. Therefore, it is likely that the potentiation by CCK antagonists of the anti-exploratory effect of CCK-8 is related to the suppression of motor activity. This peculiar interaction between CCK-8 and CCK antagonists could be explained in the light of the opposite role of CCKA and CCKB receptors in the regulation of motor activity in mice.

An overview of the clinical pharmacokinetics of x-ray contrast media.

Pharmacokinetic studies of contrast media are usually performed as preclinical trials in anaesthetised animals; however, results in humans have also been reported for this type of compounds. This paper reviews the existing data about x-ray contrast media in humans. In some cases, animal data are used in areas where no human data are available. The administration of contrast media is generally made via the intravenous, intra-arterial or intrathecal route. Diagnostic procedures are based on differential distribution to organs and between normal and abnormal tissue. Data are available for iodixanol, iohexol, iopamidol, iopromide, iothalamate and ioxaglate, but the kinetic distribution of all contrast media is similar. With the exception of biliary contrast agents, all compounds display limited plasma protein binding and do not undergo biotransformation. From the pharmacokinetic viewpoint, the main area of interest for these compounds is elimination. The majority of the data were obtained with iopamidol (of which 66 to 72% of the dose is excreted in the urine), iohexol, ioxaglate and iopromide. Some studies were performed in patients with renal impairment: in this case, metabolic clearance was abnormally elevated, suggesting the existence of significant compensatory factors such as hepatic metabolism, enterohepatic circulation and biliary elimination. New compounds, such as iodinated polymers for x-ray perfusion imaging and iopromide- or metrizamide-containing liposomes allowing liver enhancement are discussed.

Effects of acute treatment with paroxetine, citalopram and venlafaxine in vivo on noradrenaline and serotonin outflow: a microdialysis study in Swiss mice.

1. This study investigated whether a single administration of a range of doses (1, 4 and 8 mg kg-1, i.p.) of paroxetine, citalopram or venlafaxine may simultaneously increase extracellular levels of 5-HT ([5-HT]ext) and noradrenaline ([NA]ext) by using in vivo microdialysis in the frontal cortex (FCx) of awake, freely moving Swiss mice. 2. In vivo, paroxetine induced similar increases in cortical [5-HT]ext at the three doses tested, and induced a statistically significant increase in cortical [NA]ext at 4 and 8 mg x kg-1. Citalopram increased neither [5-HT]ext nor [NA]ext at the lowest dose, but increased both neurotransmitter levels at 4 and 8 mg x kg-1. At these doses, citalopram induced greater increases in cortical [5-HT]ext than in [NA]ext. Venlafaxine increased [5-HT]ext and [NA]ext to about 400 and 140% of the respective basal values at 8 mg kg-1. 3. Citalopram and paroxetine have the highest potency to increase cortical [5-HT]ext and [NA]ext, respectively. In addition, the rank of order of efficacy of these antidepressant drugs to increase [5-HT]ext in vivo in the FCx of mice was as follows: venlafaxine>citalopram>paroxetine, while the efficacy to increase cortical [NA]ext in mice of paroxetine and citalopram is similar, and greater than that of venlafaxine. 4. In conclusion, extracellular levels of cortical [NA]ext increase with the highest doses of the very selective SSRI citalopram, as well as with the very potent SSRI paroxetine. Surprisingly, the SNRI venlafaxine increased cortical [5-HT]ext to a greater extent rather than [NA]ext in the range of doses studied in mice.

Drug mechanisms in anxiety.

The most common and successful therapyfor the majority of patients suffering from anxiety is treatment with benzodiazepines (BZDs). The problem of drug-induced dependency following treatment with these drugs may be avoided by developing more selective and specific BZD compounds, such as 2,3-substituted BZDs. Alternative approaches to the treatment of anxiety include the following: (i) antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), which are active in treating most anxiety disorders, including GAD; (ii) metabotropic glutamate (mGluR2) receptor agonists, which negatively modulate glutamate neurotransmission, and CRF antagonists, which have been proposed to exhibit anxiolytic properties; (iii) 5-HT1A receptor agonists which have demonstrated anxiolytic effects in clinical studies, although preclinical studies have reported weak or variable effects; (iv) 5-HT moduline antagonists, as well as 5-HT2C receptor antagonists, which may have anxiolytic properties; and, finally, (v) other approaches which are under investigation, including CCK2 antagonists.

Dose-dependent influence of buspirone on the activities of selective serotonin reuptake inhibitors in the mouse forced swimming test.

Recent clinical data suggest that buspirone may enhance the efficacy and/or reduce the latency to therapeutic effect of selective serotonin reuptake inhibitors (SSRIs) in unipolar major depressive disorder. The present study, using the mouse forced swimming test, was performed to investigate further the mechanisms involved in the potential antidepressant-enhancing effects of buspirone. Prior administration of buspirone (0.06 mg kg(-1), i.p.) significantly enhanced the anti-immobility effects of subactive doses of fluvoxamine (4 mg kg(-1), i.p.; P < 0.01), paroxetine (4 mg kg(-1), i.p.; P < 0.01), citalopram (4 mg kg(-1), i.p.; P < 0.01) and sertraline (2 mg kg(-1), i.p.; P < 0.01) in the forced swimming test. However, pretreatment with buspirone did not induce antidepressant-like effects when tested in combination with fluoxetine (4 mg kg(-1), i.p.). Each antidepressant tested reduced immobility time in the forced swimming test [citalopram (16 mg kg(-1), i.p.; P < 0.01), fluoxetine (32 mg kg(-1), i.p.; P < 0.01), fluvoxamine (32 mg kg(-1), i.p.; P < 0.01), paroxetine (16 mg kg(-1), i.p.; P < 0.01) and sertraline (16 mg kg(-1), i.p.; P < 0.01)]. Pretreatment with buspirone (0.5 mg kg(-1), i.p.), or its major metabolite 1-PP (0.5 mg kg(-1), i.p.), attenuated all SSRI-induced anti-immobility effects (P < 0.01). Concomitant studies of locomotor activity ruled out any stimulant or sedative effects of the interactions. The results of the present study suggested that low dose buspirone enhanced the activity of subactive doses of SSRIs in the mouse forced swimming test, probably via an action at 5-HT1A receptors. On the other hand, a high dose of buspirone attenuated the antidepressant-like effects of active doses of these drugs, possibly via the generation of an active metabolite (1-PP) acting at alpha2-adrenoreceptors.