Caroline McGrath

The heritability of melatonin secretion and sensitivity to bright nocturnal light in twins

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.

Low doses of lithium carbonate reduce melatonin light sensitivity in healthy volunteers.

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 effect of venlafaxine treatment on the behavioural and neurochemical changes in the olfactory bulbectomised rat.

Abstract 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.

Neurochemical effects of the enantiomers of mirtazapine in normal rats

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 beta1-adrenoceptor density, although this failed to reach significance. A significant decrease in beta1-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.

Treatment of anxiety during pregnancy: Effects of psychotropic drug treatment on the developing fetus

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.

An investigation of the effect of tacrine and physostigmine on spatial working memory deficits in the olfactory bulbectomised rat

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.

Mechanisms underlying the speed of onset of antidepressant response

Depression is an incapacitating disorder with serious health and economic consequences. It has an estimated cost of more than

The benzodiazepines: a brief review of pharmacology and therapeutics

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.

Neuropsychological Study of Underweight and 'Weight-Recovered' Anorexia Nervosa Compared with Bulimia Nervosa and Normal Controls

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.