Identification of the perpetrator imperatorin in Xin-yi-san-theophylline interaction: observed and predicted herb-drug interaction in rats.

OBJECTIVES: Theophylline is a bronchodilator with a narrow therapeutic index and primarily metabolised by cytochrome P450 (CYP) 1A2. Xin-yi-san (XYS) is a herbal formula frequently used to ameliorate nasal inflammation. This study aimed to investigate the effects of XYS and its ingredient, imperatorin, on theophylline pharmacokinetics in rats. METHODS: The kinetics of XYS- and imperatorin-mediated inhibition of theophylline oxidation were determined. Pharmacokinetics of theophylline were analysed. Comparisons were made with the CYP1A2 inhibitor, fluvoxamine. KEY FINDINGS: XYS extract and its ingredient, imperatorin, non-competitively inhibited theophylline oxidation. Fluvoxamine (50 and 100 mg/kg) and XYS (0.5 and 0.9 g/kg) significantly prolonged the time to reach the maximum plasma concentration (tmax) of theophylline by 3-10 fold. In a dose-dependent manner, XYS and imperatorin (0.1-10 mg/kg) treatments significantly decreased theophylline clearance by 27-33% and 19-56%, respectively. XYS (0.9 g/kg) and imperatorin (10 mg/kg) significantly prolonged theophylline elimination half-life by 29% and 142%, respectively. Compared with the increase (51-112%) in the area under curve (AUC) of theophylline by fluvoxamine, the increase (27-57%) by XYS was moderate. CONCLUSIONS: XYS decreased theophylline clearance primarily through imperatorin-suppressed theophylline oxidation. Further human studies are essential for the dose adjustment in the co-medication regimen.

Pediatric considerations for pharmacogenetic selective serotonin reuptake inhibitors clinical decision support.

Pharmacogenetic testing for psychiatry is growing at a rapid pace, with multiple sites utilizing results to help clinical decision-making. Genotype-guided dosing and drug selection have been implemented at several sites, including Vanderbilt University Medical Center, where clinical decision support (CDS) based on pharmacogenetic results went live for selective serotonin reuptake inhibitors in 2020 for both adult and pediatric patients. Effective and appropriate implementation of CYP2D6- and CYP2C19-guided CDS for the pediatric population requires consideration of the evidence for the pharmacogenetic associations, medication indications, and appropriate alternative therapies to be used when a pharmacogenetic contraindication is identified. In this article, we review these pediatric pharmacogenetic considerations for selective serotonin reuptake inhibitor CDS. We include a case study, the current literature supporting clinical recommendations, considerations when designing pediatric CDS, future implications, and examples of sertraline, (es)citalopram, paroxetine, and fluvoxamine alerts.

Comparing the Effects of a Herbal Drug based on Echium Amoenum With Fluvoxamine in the Treatment of Adolescents with Obsessive-compulsive Disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a severe and debilitating neuropsychiatric condition. Although selective serotonin reuptake inhibitors, tricyclic antidepressants, and cognitive- behavioral therapy are the first-line medication and treatment for OCD, an estimated 30% of patients are treatment-resistant, and complete functional recovery is rare. Natural products as adjuvant or alternative therapies should be examined to find safer and more effective ways to manage OCD. OBJECTIVES: To investigate the potential benefits of a combined herbal drug based on Echium amoenum in treating OCD. METHODS: Design and Setting: In the psychiatric clinics of Mashhad University of Medical Sciences, 40 patients who met the criteria for the obsessive-compulsive disorder based on DSM-5 were studied in a parallel, double-blind, randomized clinical trial. INTERVENTION: Subjects were randomly assigned to receive Echium amoenum-Melissa officinalis syrup and fluvoxamine or placebo syrup and fluvoxamine for 8 weeks. OUTCOME MEASURES: The efficacy of treatment and recurrence of disease were surveyed and compared according to the Yale-Brown Obsessive Compulsive Scale at weeks 0, 4, and 8. RESULTS: Evaluation at the 4th and 8th week showed no significant differences between the two groups (p-value = 0.11, p-value = 0.445, respectively). At the 8th week of treatment, patients in the intervention group showed a remarkable reduction in scores on the Yale-Brown Obsessive-Compulsive Scale questionnaire (p- value= 0.003), and patients in the control group didn't ((p- value= 0.180). This study showed that the E.amoneum-M.officinalis syrup was not significantly more efficacious than the fluvoxamine tablet, but the intervention group showed a significant improving trend (p-value= 0.001). CONCLUSION: While monotherapy is usually the gold standard methodology, combination or augmentation therapy may also be of merit. Consequently, studies with larger sample sizes and the inclusion of para-clinical assessments such as serologic tests can further shed light on the mechanism of action of the E. amoneum- M. officinalis syrup and deepen our understanding of its effects.

Yokukansan, a traditional Japanese herbal medicine, enhances the anxiolytic effect of fluvoxamine and reduces cortical 5-HT2A receptor expression in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Yokukansan is a traditional Japanese herbal medicine that has been approved in Japan as a remedy for neurosis, insomnia, and irritability in children. It has also been reported to improve behavioral and psychological symptoms in patients with various forms of dementia. AIM OF THE STUDY: To evaluate the usefulness of co-treatment with an antidepressant and an herbal medicine in the psychiatric field, the current study examined the effect of yokukansan on the anxiolytic-like effect of fluvoxamine in mice. MATERIALS AND METHODS: The anxiolytic-like effect in mice was estimated by the contextual fear conditioning paradigm. Contextual fear conditioning consisted of two sessions, i.e., day 1 for the conditioning session and day 2 for the test session. The expression levels of 5-HT1A and 5-HT2A receptor in the mouse brain regions were quantified by western blot analysis. RESULTS: A single administration of fluvoxamine (5-20 mg/kg, i.p.) before the test session dose-dependently and significantly suppressed freezing behavior in mice. In the combination study, a sub-effective dose of fluvoxamine (5 mg/kg, i.p.) significantly suppressed freezing behavior in mice that had been repeatedly pretreated with yokukansan (0.3 and 1 g/kg, p.o.) once a day for 6 days after the conditioning session. Western blot analysis revealed that the expression level of 5-HT2A receptor was specifically decreased in the prefrontal cortex of mice that had been administered yokukansan and fluvoxamine. Furthermore, microinjection of the 5-HT2A receptor antagonist ketanserin (5 nmol/mouse) into the prefrontal cortex significantly suppressed freezing behavior. CONCLUSION: The present findings indicate that repeated treatment with yokukansan synergistically enhances the anxiolytic-like effect of fluvoxamine in the contextual fear conditioning paradigm in mice in conjunction with a decrease in 5-HT2A receptor-mediated signaling in the prefrontal cortex. Therefore, combination therapy with fluvoxamine and yokukansan may be beneficial for the treatment of anxiety disorders.

Cytochrome P450 2C19 inhibitory activity of common berry constituents.

The cytochrome P450 enzyme CYP2C19 is involved in the metabolism of many commonly prescribed drugs, including proton pump inhibitors, antiepileptics and antidepressants. CYP2C19 inhibitors from food and food supplements may augment the toxicity of these agents and lead to noncompliance with treatment. The present investigation addresses CYP2C19 inhibition by 18 berry constituents using a chemiluminescent assay. Test compounds displayed inhibitory properties in a concentration-dependent fashion, with IC(50) values ranging from 20.2 microM up to >316 microM. In the order of decreasing effect size, anthocyanidins were followed by anthocyanidin-monoglycosides and procyanidins. Anthocyanidin-diglucosides exhibited weak and biphasic effects. When compared with the CYP2C19 inhibitor fluvoxamine, the flavonoids under study were 50- to 750-fold less potent. It is concluded that the above natural substances are moderate to poor inhibitors of CYP2C19 in vitro.

Fluvoxamine exerts anorexic effect in 5-HT2C receptor mutant mice with heterozygous mutation of beta-endorphin gene.

Serotonin (5-hydroxytryptamine; 5-HT) 2C receptors and the downstream melanocortin pathway are suggested to mediate the anorexic effects of m-chlorophenylpiperazine (mCPP) and fenfluramine. We previously reported that fluvoxamine, a selective serotonin reuptake inhibitor, together with pharmacological inactivation of 5-HT2C receptors exert feeding suppression through activation of 5-HT1B receptors in mice. Here, we report that fluvoxamine exerted anorexic effects in 5-HT2C receptor mutant mice with heterozygous mutation of beta-endorphin gene (2CREnd mice), whereas fluvoxamine had no effect on food intake in age-matched wild-type mice and 5-HT2C receptor mutant mice, which are associated with decreases in hypothalamic proopiomelanocortin (POMC) expression. mCPP suppressed food intake in 5-HT2C receptor mutant mice, 2CREnd mice and age-matched wild-type mice. These results suggest that fluvoxamine-induced feeding suppression requires a perturbation of 5-HT2C receptor and beta-endorphin signalling plus functional hypothalamic POMC activity, whereas mCPP-induced feeding suppression does not always require functional 5-HT2C receptor, beta-endorphin, and POMC activity in mice.

Selective serotonin reuptake inhibitors modify physiological gastrointestinal motor activities via 5-HT2c receptor and acyl ghrelin.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat anxiety and depressive disorders. These agents may cause upper gastrointestinal (GI) symptoms that lead to their discontinuation. We examined whether SSRIs modify physiologic GI motor activities in freely moving rats. METHODS: The SSRIs fenfluramine, fluvoxamine, paroxetine, and fluoxetine were administered to 24-hour food-deprived rats, and then GI motility was measured in conscious, freely moving rats using a strain gauge force transducer method. Plasma acyl ghrelin levels were determined by enzyme immunoassay. RESULTS: Plasma acyl ghrelin levels were analyzed in conjunction with fasted motor activities. Acyl ghrelin was increased in association with the occurrence of Phase III-like contractions of the migrating motor complex in the antrum and duodenum. SSRIs decreased acyl ghrelin and changed Phase III-like contractions to fed-like motor activities. Both effects were blocked by 5-HT2c, but not 5-HT1b, receptor antagonist. Neither melanocortin 4 nor the 3/4 receptor antagonists blocked this motor effect, although they restored the anorexia induced by SSRIs. The improving effect on GI motility by 5-HT2c receptor (5-HT2cR) antagonist disappeared after treatment with a growth-hormone secretagogue receptor antagonist, whereas ghrelin or ghrelin-releasing drug such as TJ-43 changed SSRI-induced fed-like motor activities to fasted activities. CONCLUSIONS: SSRIs have inhibitory effects on acyl ghrelin and GI motor activities through 5-HT2cR. Our study identifies the importance and divergence of central 5-HT2cR pathways that regulate GI motor activities through ghrelin and feeding/energy metabolism via melanocortin 4 receptor signaling.

Fluvoxamine inhibits weight gain and food intake in food restricted hyperphagic Wistar rats.

The effects of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), were studied in normophagic and food-restriction-induced hyperphagic middle-aged Wistar rats. Normophagic intact Wistar rats were given fluvoxamine (100 mg/kg/d, per os (p.o.)) or vehicle for 10 d. Hyperphagic middle-aged Wistar rats were subjected to 10 d of food restriction; they were allowed to refeed for 10 d, with ad libitum food access and administered fluvoxamine (100 mg/kg/d, p.o.) or vehicle during the 10-d refeeding period. Fluvoxamine administration to normophagic middle-aged Wistar rats affected neither their weight nor food intake. However, administration to food-restricted rats showed inhibitory effects of weight gain and food intake during 10 d of refeeding. Fluvoxamine-treated rats showed significantly lower neuropeptide Y (NPY) immunostaining levels in the paraventricular nucleus (PVN) and dorsomedial hypothalamic nucleus (DMH) than untreated controls. Hypophagic and weight-inhibiting effects of fluvoxamine might be mediated via decreased NPY in PVN and DMH. These results suggest that the appetite-controlling effect of fluvoxamine might be responsive to the rats' appetite condition.

Chronic fluoxetine increases cytosolic phospholipase A(2) activity and arachidonic acid turnover in brain phospholipids of the unanesthetized rat.

RATIONALE: Fluoxetine is used to treat unipolar depression and is thought to act by increasing the concentration of serotonin (5-HT) in the synaptic cleft, leading to increased serotonin signaling. The 5-HT(2A/2C) receptor subtypes are coupled to a phospholipase A(2) (PLA(2)). We hypothesized that chronic fluoxetine would increase the brain activity of PLA(2) and the turnover rate of arachidonic acid (AA) in phospholipids of the unanesthetized rat. MATERIALS AND METHODS: To test this hypothesis, rats were administered fluoxetine (10 mg/kg) or vehicle intraperitoneally daily for 21 days. In the unanesthetized rat, [1-(14)C]AA was infused intravenously and arterial blood plasma was sampled until the animal was killed at 5 min and its brain was subjected to chemical, radiotracer, or enzyme analysis. RESULTS: Using equations from our fatty acid model, we found that chronic fluoxetine compared with vehicle increased the turnover rate of AA within several brain phospholipids by 75-86%. The activity and protein levels of brain cytosolic PLA(2) (cPLA(2)) but not of secretory or calcium-independent PLA(2) were increased in rats administered fluoxetine. In a separate group of animals that received chronic fluoxetine followed by a 3-day saline washout, the turnover of AA and activity and protein levels of cPLA(2) were not significantly different from controls. The protein levels of cyclooxygenases 1 and 2 as well as the concentration of prostaglandin E(2) in rats chronically administered fluoxetine did not differ significantly from controls. CONCLUSION: The results support the hypothesis that fluoxetine increases the cPLA(2)-mediated turnover of AA within brain phospholipids.

Co-administration of ramelton and fluvoxamine to increase levels of interleukin-2.

Ramelton is a medication recently approved by the FDA for treatment of insomnia. Ramelton is an analogue of melatonin with a higher affinity even than that of the natural ligand. Clinically this potentially strong effect of the ligand is blunted by the fact that upon oral ingestion there is first pass metabolism of greater than 95%. This liver metabolism is mediated by the CYP1A2 enzyme. It turns out that the medication fluvoxamine approved by the FDA for the treatment of obsessive compulsive disorder is a potent inhibitor of the CYP1A2 enzyme, with the effect that co-administration of ramelton and fluvoxamine increases blood levels of ramelton by 100-200 fold. It turns out that lymphocytes bear the melatnonin receptors and stimulation of these receptors on lymphocytes cause the lymphocytes to elaborate the pro-inflammatory cytokine interleukin-2 (Il-2). Thus, here we point out that co-administration of ramelton and modest doses of fluvoxamine may be able to smoothly produce increased levels of Il-2, this may be useful in diseases and conditions such as metastatic cancer and maintenance of suppression of the HIV virus.

The spermicidal and antitrichomonas activities of SSRI antidepressants.

The study investigated spermicidal and antitrichomonas activities of selective serotonin reuptake inhibitor (SSRI) antidepressants with a view to generate new lead for development of dual-function spermicidal microbicides, which is an urgent global need. Fluoxetine, Sertraline, and Fluvoxamine exhibited both spermicidal and anti-STI (antitrichomonas) activities in vitro, whereas Paroxetine and Citalopram showed only the spermicidal activity. Fluoxetine exhibited better activity profile than the other antidepressant drugs with its spermicidal and antitrichomonas activities being comparable to that of the OTC contraceptive Nonoxynol-9. The non-detergent nature of Fluoxetine and a much lower spermicidal ED50 value (than N-9) may add considerably to its merit as a candidate for microbicidal contraceptive. Thus, the antidepressants exhibiting both spermicidal and antitrichomonas activities might provide useful lead for the development of novel, dual-function spermicidal contraceptives.

Effects of chronic treatment with fluvoxamine and paroxetine during adolescence on serotonin-related behavior in adult male rats.

Selective Serotonin Reuptake Inhibitors (SSRIs) are designed to treat adults, but are increasingly prescribed for adolescents. SSRIs might cause permanent changes in serotonin-related behavior in adolescents, since their serotonergic system is still developing. Male Wistar rats were treated with paroxetine (15 mg/kg p.o.) or fluvoxamine (30 mg/kg p.o.) throughout adolescence. After a washout period their behavior in the elevated plus-maze, prepulse inhibition test, Forced swimming test and elevated T-maze were studied. In addition, the effects of the 5-HT(1A) receptor agonist 8-OH-DPAT on sexual behavior and lower lip retraction were measured. Paroxetine mildly inhibited weight gain during treatment. Both SSRIs caused a reduction in ejaculation frequency and in time spent on the open arm of the elevated plus-maze in adult rats. Fluvoxamine slightly increased avoidance latency in the elevated T-maze compared to paroxetine. No differences between the groups were found in the other tests. Apparently, chronic treatment with SSRIs during adolescence may cause mild changes in adult behavior.

Approach to novel functional foods for stress control 4. Regulation of serotonin transporter by food factors.

Serotonin transporters (SERTs) are pre-synaptic proteins specialized for the clearance of serotonin following vesicular release at central nervous system (CNS) and enteric nervous system synapses. SERTs are high affinity targets in vivo for antidepressants such as serotonin selective reuptake inhibitors (SSRIs). These include 'medical' psychopharmacological agents such as analgesics and antihistamines, a plant extract called St John's Wort (Hypericum). Osteoclasts are the primary cells responsible for bone resorption. They arise by the differentiation of osteoclast precursors of the monocyte/macrophage lineage. The expression of SERTs was increased in RANKL-induced osteoclast-like cells. Using RANKL stimulation of RAW264.7 cells as a model system for osteoclast differentiation, we studied the direct effects of food factor on serotonin uptake. The SSRIs (fluoxetine and fluvoxamine) inhibited markedly (approximately 95%) in serotonin transport in differentiated osteoclast cells. The major components of St. John's Wort, hyperforin and hypericine were significantly decreased in serotonin transport activity. Thus, a new in vitro model using RANKL-induced osteoclast-like cells may be useful to analyze the regulation of SERT by food factors and SSRIs.

Role of extracellular serotonin levels in the effect of 5-HT1B receptor blockade.

The release of serotonin (5-HT) at serotonergic nerve terminals is regulated by 5-HT(1B) autoreceptors. Several studies have reported that the effects of selective 5-HT reuptake inhibitors (SSRIs) on extracellular 5-HT are augmented by 5-HT(1B) receptor antagonists, whereas administration of these antagonists alone do not enhance 5-HT levels. It has been suggested that 5-HT(1B) receptors have low basal endogenous activity and therefore elevated endogenous 5-HT levels are needed to elicit an effect of 5-HT(1B) receptor antagonists. To test this hypothesis, different strategies were used to enhance 5-HT levels in the rat frontal cortex to assess the effects of locally applied NAS-181, a new selective 5-HT(1B) receptor antagonist. Blockade of 5-HT(1B) receptors with NAS-181 dose dependently augmented 5-HT levels when 5-HT levels were enhanced by a SSRI. No additional effect of NAS-181 on 5-HT output was found when 5-HT levels were enhanced by KCl depolarization-induced release or by preventing degradation of 5-HT with the monoamine oxidase inhibitor pargyline. In the presence of fluvoxamine, the increased 5-HT release evoked by KCl depolarization was augmented by NAS-181, supporting the idea that blockade of 5-HT transporters is necessary to measure an effect of 5-HT(1B) receptor blockade. In conclusion, the results provide circumstantial evidence that the effect of a 5-HT(1B) receptor antagonist depends on extracellular 5-HT levels, but strongly suggest that additional 5-HT reuptake inhibition is required to detect any effect of 5-HT(1B) receptor antagonist on 5-HT levels by in vivo microdialysis.

Reduction of central poststroke pain with the selective serotonin reuptake inhibitor fluvoxamine.

To investigate the effect of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine on central poststroke pain (CPSP), fluvoxamine (25 to 125 mg daily) was given to 31 patients. Although 3 patients dropped out within 1 week, 28 patients who received fluvoxamine for 2 to 4 weeks showed a significant reduction in the visual analog scale (VAS) for pain from 7.7 +/- 2.2 to 6.0 +/- 3.4 (p < .01). This improvement in VAS was significant in patients within less than 1 year after stroke, but not in those with a duration of more than 1 year. Zung's Self-rating Depression Scale (SDS) was also significantly improved after treatment, but there was no significant correlation between the changes in VAS and SDS. Although this is not a double-blind, placebo-controlled trial, these results suggest that fluvoxarnine is useful for the control of CPSP regardless of depression when used relatively early after stroke.

The role of selective serotonin reuptake inhibitors in reducing alcohol consumption.

Preclinical and clinical studies demonstrated an inverse relationship between serotonergic activity and alcohol consumption. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine, citalopram, and fluvoxamine have subsequently been examined for their ability to reduce alcohol consumption in alcoholic subjects. Interindividual variability in response to SSRIs is large, with reductions in alcohol consumption ranging from 10% to more than 70%. Several factors, including gender, alcoholic subtype, and extent of drinking, appear to affect the treatment efficacy of the SSRIs. A significant challenge for researchers is to identify the subject variables that predict treatment response, providing a basis for guiding alcohol-dependent individuals to the treatment that is most likely to be effective for them. This article reviews the available clinical studies, discusses possible mechanisms of action for the SSRIs, and describes a model for predicting treatment responses in alcoholic subjects.

Increased bioavailability of oral melatonin after fluvoxamine coadministration.

BACKGROUND: Fluvoxamine, a selective serotonin reuptake inhibitor, is known to elevate melatonin serum concentrations. It has not been clear whether these effects might be attributed to an increased melatonin production or to an decreased elimination of melatonin. The latter hypothesis was tested by this study. METHODS: Five healthy male volunteers (one CYP2D6 poor metabolizer) received 5 mg melatonin either with or without coadministration of 50 mg fluvoxamine. Serum concentrations of melatonin and fluvoxamine were assessed from 0 to 28 hours after melatonin intake. RESULTS: Coadministration of fluvoxamine, on average, led to an 17-fold higher (P < .05) area under concentration-time curve (AUC) and a 12-fold higher (P < .01) serum peak concentration (Cmax) of melatonin. The terminal elimination half-life was not significantly affected. The AUC and Cmax of fluvoxamine were about three times higher and the half-life was about two times higher in the poor metabolizer. There was a correlation (r = 0.63; P < .01) between the melatonin and fluvoxamine serum concentrations. The poor metabolizer was found to have a more pronounced and longer-lasting effect of fluvoxamine on the pharmacokinetics of melatonin. CONCLUSION: This study showed an increase in the bioavailability of oral melatonin by coadministration of fluvoxamine. The effects of fluvoxamine on the melatonin serum concentrations in patients with depression might therefore be caused by inhibition of the elimination of melatonin and not attributable to an increased production of melatonin.

Comparison of buspirone with diazepam and fluvoxamine on aversive classical conditioning in humans.

The effects of buspirone, fluvoxamine and diazepam were investigated, using healthy volunteers, in an aversive conditioning paradigm, a putative model for conditioned anxiety. The main prediction was that buspirone, an anxiolytic agent which reduces activity in serotonin (5-hydroxytryptophan, 5-HT) neurones, would attenuate aversively conditioned skin conductance responses. Skin conductance responses were recorded to 10 neutral tones (habituation phase). Tone 11 was immediately followed by a 1-s 90-dB aversive white noise (unconditioned stimulus). The conditioning trial reinstated responding to a second presentation of the tones (extinction phase). Skin conductance response amplitude, inter-response level and spontaneous fluctuations were recorded. There were five treatment groups comprising five men and five women. One control group took placebo, another control group received nothing; there was no effect of placebo on any measure. Diazepam (2 mg, p.o.), a positive comparator, markedly reduced the amplitude of skin conductance responses at all phases of the experiment, but only in women. Buspirone (5 mg, p.o.) had the predicted effect of accelerating extinction but also of unexpectedly accelerated habituation of skin conductance responses. There was a trend to reduce spontaneous fluctuations and no effect on skin conductance level. The effects of buspirone were thus specific to responses to stimuli. Fluvoxamine (25 mg, p.o.) had similar effects to buspirone and diazepam in women. An action common to buspirone, fluvoxamine and diazepam, which may account for their shared effect on conditioned autonomic responses, is the suppression of neural activity in the dorsal raphe nucleus. It is argued that enhanced habituation must involve a different mechanism, such as enhanced 5-HT1A function in the terminal fields of the median raphe nucleus.

Behavioural effects in mice of subchronic chlordiazepoxide, maprotiline, and fluvoxamine. I. Social interactions.

The present study compares the effects of subchronic administration (daily. 21 days) of chlordiazepoxide (CD), maprotiline and fluvoxamine on the behavior of male mice during dyadic social interactions. Maprotiline like chlordiazepoxide, stimulated aggression at 4 mg/kg and 2 mg/kg respectively (intermediate dose levels), whereas effects of fluvoxamine (3-8 mg/kg) were mainly sedative. Non-social activity was reduced by CD at 4 and 8 mg/kg and by maprotiline at 0.5 mg/kg. At the highest dose tested (10 mg/kg), maprotiline increased immobility, resembling the effects of fluvoxamine, while at 2 mg/kg, it reduced social investigation. Thus, despite some commonalities, there were several differences in behavioral profile of the compounds tested. Data are discussed in relation to the efficacy of each of these compounds in treating anxiety and depressive disorders.

Behavioural effects in mice of subchronic chlordiazepoxide, maprotiline and fluvoxamine. II. The elevated plus-maze.

In view of apparent commonalities in the aetiology, symptomatology, and pharmacotherapy of anxiety and depressive disorders, the present study compares the effects of the benzodiazepine, chlordiazepoxide (1.0-8.0 mg/kg), the selective noradrenaline (NA) reuptake inhibitor, maprotiline (0.5-10.0 mg/kg), and the serotonin (5-HT)-selective reuptake inhibitor, fluvoxamine (2.0-8.0 mg/kg), on the behaviour of mice in the elevated plus-maze test of anxiety. To more accurately reflect the clinical situation, subjects were treated daily for 21 days prior to testing, and comprehensive behavioural profiles were obtained through the application of an ethological scoring technique. Results show that subchronic treatment with chlordiazepoxide produced clear anxiolytic-like effects at the highest dose tested, coupled with an inhibition of risk assessment over the entire dose range. With the exception of risk assessment measures, anxiolytic-like effects were also seen with a low dose (0.5 mg/kg) of maprotiline: these effects were lost at higher doses. In contrast to these data, fluvoxamine produced minimal behavioural change under present test conditions. Findings are discussed in relation to the relative efficacy of selective monoamine. reuptake inhibitors in the treatment of anxiety disorders, and the nature of anxiety evoked in mice by exposure to the elevated plus-maze.