Pregnancy is a time of great emotional change for a woman, producing increased stress and anxiety. Medication may be required for the treatment of anxiety disorders at this time. Given the fact that psychotropic drugs readily cross the placenta and could have important implications for the developing fetus, it is necessary to balance the possible effects of medication against the potential effects to both the mother and fetus if the anxiety disorder is left untreated. Despite the widespread use of psychotropic drugs such as benzodiazepines and antidepressants during pregnancy, there is a paucity of information regarding the effect of such exposure on the developing fetus. From a review of the literature it is clear that the issue of safety of psychotropic drugs during pregnancy is far from resolved. While some of the findings from animal studies are alarming, these studies cannot be directly extrapolated to humans. In addition, varying sample sizes and multiple drug exposures further complicate interpretation of human studies. Nonpharmacological treatments such as cognitive behavioural therapy should be employed whenever possible for the treatment of anxiety disorders during pregnancy. However, if medication is required pregnant women should be prescribed the lowest dosage for the minimum amount of time.

OBJECTIVE:To compare executive, memory and visuospatial functioning of DSM-IV anorexia nervosa (AN), bulimia nervosa (BN), and normal controls (NC). METHOD:A comparison of women involving: (i) 16 AN with body mass indices (BMI) < or = 17.5 kg/m(2); (ii) 12 AN with BMI > 18.5 kg/m(2) for at least 3 months; (iii) 13 BN; and (iv) 16 NC participants was performed with groups of similar age and intelligence. Groups were assessed with EDE-12, MADRS, HAMA, Cognitive Drug Research (CDR) battery, and Bechara tasks. RESULTS:Significant impairments in CDR Power of Attention were present in underweight AN and BN participants. CDR Morse Tapping was significantly impaired in all clinical groups. The BN and weight-recovered AN groups were significantly impaired on CDR immediate word recall. The BN group alone was significantly impaired on CDR delayed word recall. CONCLUSION:Attentional impairment is similar in AN and BN. Impaired motor tasks in AN persist after "weight-recovery" and are similar to impairments in BN. BN may be discriminated from AN on word recall.

The super-sensitivity of the neurohormone melatonin to light in patients with bipolar disorder provides evidence of the circadian nature of the disorder. This response has been proposed as an endophenotype for identifying people at risk of the disorder and guiding investigations of molecular genetic targets. However, before this response is used as an endophenotypic marker, the heritable nature of melatonin sensitivity in the normal population must be established. The aim of this study was to investigate the heritability of nocturnal melatonin secretion and sensitivity to light in monozygotic and dizygotic twins with no psychiatric history. This study investigated overall melatonin levels (between 2000 and 2400 h) and suppression by 500 lx of light (between 2400 and 0100 h) in 20 pairs of twins (nine monozygotic, 11 dizygotic). The results indicate that melatonin secretion is highly heritable with secretion in one twin being a significant predictor of secretion in their twin in both monozygotic and dizygotic pairs. In relation to light sensitivity, genetic loading appears to play a significant role with the greatest concordance between monozygotic twins, followed by dizygotic twins and finally low concordance in unrelated individuals. This provides additional support for the usefulness of melatonin sensitivity to light as a potential endophenotypic marker of bipolar affective disorder.

Sensitivity of the pineal hormone melatonin to bright light at night has been posited as a putative marker of affective disorders. Research demonstrates melatonin supersensitivity to light in bipolar disorder, however the role that lithium carbonate plays in this response is unclear. This study assessed the effect of lithium on nocturnal melatonin secretion and sensitivity to light in healthy adults. Ten participants, tested on two nights, had blood samples drawn between 20:00 and 02:30 hours. On testing nights participants were exposed to 200 lux of light between 24:00 and 01:00 hours. Participants took 250 mg of lithium daily for 5 d between testing nights. The results indicated that lithium had a significant effect on sensitivity to light but not on overall melatonin synthesis. This finding has implications on the true magnitude of the melatonin light response in people with bipolar disorder and may elucidate possible mechanisms of action of lithium.

The olfactory bulbectomised (OB) rat is being increasingly used as a model of impaired learning and mnemonic functioning. In this study the model has been utilised to determine the effect of the acetylcholinesterase inhibiting compounds tacrine and physostigmine on spatial working memory deficits associated with the OB rat. One-hundred and twenty male rats were randomly allocated to OB or sham operated groups and received chronic i.p. treatment with either saline, physostigmine (0.1 mg/kg) or tacrine (0.1 and 0.3 mg/kg). Two weeks after beginning treatment animals were tested on the Morris water maze and open field test. The results indicated that the OB surgery was associated with spatial working memory disturbances that were effectively attenuated with both doses of tacrine, but not physostigmine. Increased hyperactivity and defecation was observed in OB animals in the Open-field test, however, these changes were not ameliorated by either drug treatment. The ability for tacrine but not physostigmine to attenuate OB cognitive deficits may be associated with the different half-life of these compounds. This study provides further support for the use of the OB rat as a drug discovery model for the investigation of novel therapeutic compounds that target the cholinergic system.

Objectives To assess the cognitive and psychomotor effects of single oral doses of valerian in healthy volunteers in comparison with a placebo and the hypnotic agent triazolam.Methods In a double-blind, placebo-controlled, four-way crossover study nine healthy subjects (5 males, 4 females) received in random order valerian 500 mg, valerian 1000 mg, triazolam 0.25 mg and placebo. Doses were separated by a wash-out period of at least 1 week. Subjects were tested before each dose and at 2, 4 and 8 h after the dose of each compound using the critical flicker fusion (CFF), choice reaction time (CRT), digit symbol substitution test (DSST), symbol search test (SST), digit span test (DST) and visual analogue scales of mood.Results Repeated measures ANOVA was used to examine the changes in performance on tests over time and significant effects were further analysed using simple main effects analysis with least significant difference corrections. Statistically significant differences were only noted for the cognitive tests: SST (F-(3,F-8) = 3.182, p < 0.05) and DSST (F-(3,F-8) = 9.688, p < 0.005). In both cases the differences between groups were due to the effects of triazolam.Conclusion These data confirm that at recommended therapeutic doses, triazolam has detrimental effects on cognitive processes in healthy volunteers as found in previous studies. Valerian was without effect on either cognitive or psychomotor performance in healthy volunteers at the doses used in this study. Should the hypnotic activity of valerian be confirmed in randomized double-blind trials it may be a less troublesome alternative to benzodiazepines in the treatment of insomnia. Copyright (C) 2003 John Wiley Sons, Ltd.

Depression is an incapacitating disorder with serious health and economic consequences. It has an estimated cost of more than $ 43 billion annually in the US (Greenberg et al., 1993) and by the year 2020 it will be the second leading cause of disease burden behind ischaemic heart disease (The Global Burden of Disease and Injury Series, 1996). Despite extensive research, very little is known about the aetiology of depressive illness or the mechanism of action of drugs used in its treatment. Although effective, there are a number of disadvantages to the use of antidepressants. Firstly, there is a delay of 3-4 weeks before any therapeutic effects of these drugs are seen. This is a serious problem since there is an increased incidence of suicide in depressed patients and a lifetime incidence of suicide of 15% has been reported from follow-up studies (Smith and Weissman, 1992; Norman and Leonard, 1994). Secondly, antidepressants, particularly the early generation, are often associated with unpleasant side effects such as dry mouth, blurred vision, urinary hesitancy, dizziness on standing, which reduce patient compliance. Improvements have been made with newer antidepressants which are based on the same mechanism of action. Venlafaxine blocks the reuptake of noradrenaline and serotonin but lacks the alpha 1, cholinergic and histaminergic receptor blocking properties of the TCA's, while nefazodone, the 5-HT2 receptor antagonist, has less side-effects than the SSRI's.

Stress MedicineVolume 16, Issue 4 p. 195-197 Editorial Stress induced animal models of depression Trevor R. Norman, Corresponding Author Trevor R. Norman Department of Psychiatry, Austin & Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria 3084, AustraliaDepartment of Psychiatry, Austin & Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria 3084, Australia.Search for more papers by this authorC. McGrath, C. McGrath Department of Psychiatry, Austin & Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria 3084, AustraliaSearch for more papers by this author Trevor R. Norman, Corresponding Author Trevor R. Norman Department of Psychiatry, Austin & Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria 3084, AustraliaDepartment of Psychiatry, Austin & Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria 3084, Australia.Search for more papers by this authorC. McGrath, C. McGrath Department of Psychiatry, Austin & Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria 3084, AustraliaSearch for more papers by this author First published: 05 July 2000 https://doi.org/10.1002/1099-1700(200007)16:4<195::AID-SMI880>3.0.CO;2-8Citations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume16, Issue4July 2000Pages 195-197 RelatedInformation

Benzodiazepines were first discovered in the mid 1950s when Sternbach, a medicinal chemist in New Jersey, began synthesising compounds with a bicyclic nucleus benzo-1, 4-diazepine structure. One compound, chlordiazepoxide (Fig. 1), exhibited sedative, anticonvulsant and muscle relaxant properties, which were confirmed by clinical studies and was launched as an anxiolytic in 1960 under the trade name Librium. A second compound, diazepam (valium), which was more potent and had a broader spectrum of activity than chlordiazepoxide [1], was introduced in 1963. Since then, numerous analogues of the benzodiazepine structure have been developed and introduced into clinical practice.

The study was designed to assess the potential antidepressant properties of the 5-HT1A receptor agonist, (+)-S-20499 (10 mg kg(-1) i.p.) in the olfactory bulbectomised (OB) rat. Following 2 weeks of treatment, the rats were tested in the elevated plus maze and the "open field". A characteristic hyperactive response was evident in the OB animals in the "open field" which was reversed following chronic treatment with (+)-S-20499. In the elevated plus maze an increase in the number of open arm entries and the time spent on the open arms was observed, although this failed to reach significance. A significant decrease in beta1 receptor affinity was evident following olfactory bulbectomy which was normalised by (+)-S-20499. (+)-S-20499 also significantly reduced the density of 5-HT2 receptors in the sham operated (SO) animals. These studies demonstrate the usefulness of the OB rat as a screening test for compounds with novel putative mechanisms of action, and highlights the potential antidepressant properties of (+)-S-20499.

5-HT1A receptor antagonists have recently been shown to accelerate the effects of some antidepressant drugs in clinical trials. In this study we investigate the effects of combining a full antagonist at the 5-HT1A receptor, WAY 100635 (0.2 mg/kg, SC) with the selective serotonin reuptake inhibitor (SSRI) paroxetine (5 mg/kg. SC) in the olfactory bulbectomized (OB) rat, an animal model of chronic (but not acute) antidepressant activity. Ambulation scores were measured in the open-field apparatus, following 3, 7, and 14 days of treatment. Further to the OB study, we simultaneously studied adaptive changes in 5-HT1A receptor function, utilizing alterations in the hypothermic response to the 5-HT1A receptor agonist 8-OH-DPAT. Paroxetine, in combination with WAY 100635, attenuated the hypothermic effects of 8-OH-DPAT as early as 3 days, with a full reversal evident following 7 days, whereas paroxetine, although attenuating the hypothermic effects in OB group by day 7, only reversed it fully after 14 days. Paroxetine alone and in combination with the antagonist reversed the olfactory bulbectomy-induced hyperactivity in the open field following 14 days of treatment only, this being the normal time of an "antidepressant" response in this model. However, there was no significant attenuation at any of the earlier time points. This further demonstrates that the reversal of this aspect of the olfactory bulbectomy-induced behavioral syndrome is insensitive to the potential faster onset of antidepressant action induced by 5-HT1A receptor antagonists. Nonetheless, WAY 100635, unlike previous studies with pindolol, did not interfere with the effects of the antidepressant in the model. The ability of the combination group to attenuate the hypothermic effects of 8-OH-DPAT faster than paroxetine alone, further emphasizes the role of the 5-HT1A receptor in the mechanism of action of antidepressants, and as a target for the development of faster acting antidepressants.

In the present study, the effect of chronic treatment with venlafaxine on β1 and 5-HT2 receptor populations was examined in the frontal cortex of olfactory bulbectomised (OB) and sham operated (SO) animals. The effect of these drugs on the behaviour of the animals on the elevated plus maze and the “open field” was also assessed. Removal of the bulbs resulted in a characteristic increase in locomotor activity in the OB animals in the “open field” which was reversed by chronic venlafaxine treatment. Venlafaxine produced a slight reduction in the number of open arm entries made by the OB animals although this failed to reach significance. Maximum change in temperature from baseline, following a single dose of 8-OH-DPAT (1.5 mg kg−1 SC), was used to assess the function of the 5-HT1A receptors. Chronic venlafaxine treatment had no effect on the hypothermic response to 8-OH-DPAT in the present study. A decrease in the affinity of β1-adrenoceptors was found following olfactory bulbectomy and this was normalised by treatment with venlafaxine. No bulbectomy-induced changes were evident 32 days post surgery in β1-adrenoceptor density; however, chronic treatment with venlafaxine significantly reduced the density of these receptors in the OB animals. Olfactory bulbectomy did not produce any changes in 5-HT2 receptor populations but venlafaxine administration significantly reduced the density of these receptors in both SO and OB animals. The findings of the present study further validate the usefulness of the OB as an animal model, for the detection of antidepressants from a wide variety of classes.

The present study was designed to examine the neurochemical effects of (±)-mirtazapine (10 mg kg−1 i.p.) and its enantiomers in rats. Male Sprague–Dawley rats received either (+)-mirtazapine, (−)-mirtazapine, (±)-mirtazapine or vehicle, by intraperitoneal injection for two weeks. Maximum change in temperature from baseline, following a single dose of the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.15 mg kg−1 s.c.), was used to assess the function of the 5-HT1A receptors. Chronic drug treatment potentiated this response, with (±)-mirtazapine>(−)-mirtazapine>(+)-mirtazapine. Receptor changes were also observed with a slight decrease in β1-adrenoceptor density, although this failed to reach significance. A significant decrease in β1-adrenoceptor affinity was observed following (−)-mirtazapine treatment. All drugs tested significantly reduced the density of the 5-HT2 receptors. Results of the present study suggest that in so far as alterations in these receptor populations are important for the therapeutic action of antidepressants, neither of the enantiomers appear to be more active than the racemic mixture.

The realisation that pindolol may accelerate the effects of some antidepressant drugs in clinical trials has added extra impetus to the search for faster acting antidepressants. Currently, no animal model of depression can identify potential faster acting antidepressant drugs or drug combinations. In this study, we investigate the effects of combining pindolol (2 mg/kg, s.c., bid) with the antidepressant paroxetine (2.5 mg/kg, i.p., bid) in the olfactory bulbectomised rat, an animal model of chronic (but not acute) antidepressant activity. Ambulation scores were measured in separate groups of rats, following 3, 7 and 14 days of treatment. Further, we simultaneously study adaptive changes in 5-HT1A receptor function, utilising alterations in the hypothermic response to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Pindolol in combination with paroxetine attenuated the hypothermic effects of 8-OH-DPAT as early as 3 days with a full reversal evident following 7 days, whereas paroxetine alone did so after 14 days only. Likewise, paroxetine alone reversed the olfactory bulbectomy-induced hyperactivity in the open field following 14 days of treatment only, this being the normal time of an `antidepressant' response in this model. However, the group treated with both paroxetine and pindolol failed to reverse the hyperactive response. This suggests that a factor intrinsic to pindolol antagonises the behavioural effects of paroxetine in the olfactory bulbectomised rat. It also demonstrates that the reversal of this aspect of the olfactory bulbectomy-induced behavioural syndrome is insensitive to the potential faster onset of antidepressant action induced by pindolol. The ability of the combination group to attenuate the hypothermic effects of 8-OH-DPAT much faster further emphasises the role of the 5-HT1A receptor in the mechanism of action of antidepressants and as a target for the development of faster acting antidepressants. However, an animal model sensitive to the effects of any such compound and the actions of pindolol remains elusive.

Olfactory bulbectomised rats were treated with drugs and their rate of acquisition of a passive avoidance task was measured. The acquisition-rate, which is disturbed by the bilateral ablations, was completely restored by acute administration of fenfluramine or fluoxetine. Partial restoration was found with quipazine. Clonodine was without effect. Repeated treatments with impramine and mianserine improved passive avoidance of bulbectomised rats. Metergoline blocked these effects of imipramine and mianserin. These results indicate a serotonergic mechanism in the effect of antidepressants on olfactory bulbectomised rats.