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.

Third-generation antidepressants: do they offer advantages over the SSRIs?

Third-generation antidepressants are a group of antidepressant agents of variable action, not confined to serotonin reuptake inhibition. These agents include venlafaxine, reboxetine, nefazodone and mirtazapine. Claims have been made for these agents in terms of improved efficacy, faster speed of onset of effect and greater safety in the treatment of depression compared with previous medications, such as the selective serotonin reuptake inhibitors (SSRIs). This article reviews the evidence for these improvements. Thirty active comparator studies were reviewed involving the third-generation antidepressant agents. While there were isolated reports of improvements over comparator agents for venlafaxine, reboxetine and mirtazepine, there were no convincing differences between third-generation agents and comparators in terms of overall efficacy, relapse prevention and speed of onset. The third-generation antidepressants were, however, of equivalent safety to SSRIs and maintained improvements in safety over first-generation agents.

The effect of single oral doses of zopiclone on nocturnal melatonin secretion in healthy male volunteers.

The effects of single oral doses of zopiclone and temazepam were investigated in eight healthy male volunteers using a single blind, placebo controlled cross over study. Doses of zopiclone were 7.5 and 15 mg while the dose of temazepam was 20 mg. Each dose was separated by at least a one-week washout period. For each subject the dim light melatonin onset (DLMO) was determined on a screening night and the drugs were administered at the time of the DLMO. Melatonin concentrations were determined by radioimmunoassay from plasma samples collected throughout the night. Both temazepam and zopiclone tended to reduce the amount of melatonin secreted, as determined by the area under the plasma concentration time curve. The differences from placebo were not statistically significant (F 3.31 = 1.07, P > 0.1). Similarly a repeated measures analysis of variance on the plasma concentration-time curves did not show any statistically significant differences between drugs and placebo (F 3.28 = 1.15, P > 0.1). There was no evidence from this study of a phase shifting effect of the drugs used. The reasons for the lack of effect on melatonin may be due to the differences in potency of the interaction of these drugs with the GABA-benzodiazepine-chloride ion channel.

Chiral determination of mirtazapine in human blood plasma by high-performance liquid chromatography.

A method is described for the determination of the two enantiomers of mirtazapine in human blood plasma by high-performance liquid chromatography. Measurements were performed on drug free plasma spiked with mirtazapine and used to prepare and validate standard curves. Levels of enantiomers of mirtazapine were also measured in patients being treated for depression with racemic mirtazapine. Mirtazapine was separated from plasma by solid-phase extraction using CERTIFY columns. Chromatographic separation was achieved using a Chiralpak AD column and pre-column and compounds were detected by their absorption at 290 nm. Imipramine was used as an internal standard. The assay was validated for each analyte in the concentration range 10-100 ng/ml. The coefficient of variance was 16% and 5.5% for(+)-mirtazapine for 10 and 100 ng/ml control specimens respectively and 15% and 7.3% for mirtazapine for 10 and 100 ng/ml control specimens respectively. This assay is appropriate for use in the clinical range. The range of plasma mirtazapine concentrations from eleven patients taking daily doses of 30-45 mg of racemate was <5 to 69 ng/ml for (+)-mirtazapine and 13-88 ng/ml for (-)-mirtazapine for blood specimens collected 10-17.5 h after taking the dose.

Antidepressants and breast-feeding: a review of the literature.

For every antidepressant so far investigated in the breast milk of mothers prescribed these medications, findings indicate that some amount of drug will be excreted into the breast milk. Nursing infants will be exposed to some, usually a very low, amount of drug and drug metabolites. Levels of drug exposure to infants for the many antidepressants available are examined, discussing milk to plasma drug concentration ratios and the infant dose as a percentage of the maternal dose. Drug concentrations in infant plasma and adverse effects of drug exposures to infants are reviewed. Factors influencing the decision on whether to breast or bottle feed an infant nursed by a mother taking antidepressants are discussed, concluding that the decision needs to be made on an individual basis. The lactating mother, in consultation with her doctor, should be in a position to make an informed decision on whether or not to breast feed. Under certain circumstances the decision to bottle feed may be wise, but more commonly the advantages of breast-feeding will outweigh the very low risk of an adverse event from drug exposure to the infant.

Acute increases in night-time plasma melatonin levels following a period of meditation.

To determine whether a period of meditation could influence melatonin levels, two groups of meditators were tested in a repeated measures design for changes in plasma melatonin levels at midnight. Experienced meditators practising either TM-Sidhi or another internationally well known form of yoga showed significantly higher plasma melatonin levels in the period immediately following meditation compared with the same period at the same time on a control night. It is concluded that meditation, at least in the two forms studied here, can affect plasma melatonin levels. It remains to be determined whether this is achieved through decreased hepatic metabolism of the hormone or via a direct effect on pineal physiology. Either way, facilitation of higher physiological melatonin levels at appropriate times of day might be one avenue through which the claimed health promoting effects of meditation occur.

The effect of gender on the melatonin suppression by light: a dose response relationship.

It is well known that light is an inhibitor of pineal melatonin secretion in humans. However, the effect of gender on the melatonin suppression by dim and bright light is still controversial. The present study investigated the effect of gender on the suppression of melatonin at five light intensities (0, 200, 500, 1,000, 3,000 lux). Five healthy men and women attended five testing sessions separated by one week. At each session, subjects were exposed to light from midnight to 0100 hours in a sitting position. Blood samples where collected at regular intervals and plasma melatonin concentration was measured using a specific radioimmunoassay. No gender differences were found in melatonin suppression by light at any of the five light intensities (p > 0.1). Furthermore, the mean melatonin suppression by light in both males and females was dose dependent (17% [200 lux], 40% [500 lux], 56% [1,000 lux] and 74% [3,000 lux]). Our findings suggest that melatonin suppression by light in intensity dependent, with no gender differences in light sensitivity.

Pindolol augmentation of antidepressants: a review and rationale.

OBJECTIVE: To critically review the literature on clinical trials in which pindolol, a 5HT1A receptor antagonist, has been used to augment the effects of antidepressants in patients with depression and to examine the pharmacodynamics and pharmacokinetics that may underlie such augmentations. METHOD: The available literature from the previous 10 years relating to the clinical use of pindolol in combination with antidepressants was critically examined. This was placed in the context of its pharmacodynamic rationale, and evidence supporting its use was critically reviewed. RESULTS: A number of open-label and placebo-controlled, double-blind trials on patients with depression showed conflicting results as to the value of adding pindolol to various antidepressant regimens in reducing latency or in augmenting the antidepressant effect in treatment-resistant cases. While pre-clinical studies using electrophysiological and microdialysis techniques suggest utility in terms of increases in extracellular concentration of 5-hydroxy-tryptamine (5HT) in serotonergic projection areas, few studies have examined the possibility of drug-drug interactions and subsequent elevated plasma levels of antidepressant. CONCLUSIONS: Pre-clinical studies suggest possible advantages of pindolol augmentation of antidepressant regimens and the achievement of faster acting antidepressants. The results of investigations in patients with depression have so far been conflicting. There exists the possibility of drug-drug interaction in pindolol/antidepressant augmentation strategies which remains to be examined.

Melatonin sensitivity to dim white light in affective disorders.

Both dim and bright light has been shown to suppress the nocturnal secretion of the pineal hormone melatonin. Early reports suggests that an abnormal response to light occurs in patients with bipolar affective disorder, where as patients with major depressive disorder respond similarly to controls. It has been suggested that this abnormal sensitivity of the melatonin response to light could be a trait marker of bipolar affective disorder. However reports lack consistency. Hence, we investigated the melatonin suppression by dim light (200 lux) in patients with bipolar affective disorder, seasonal affective disorder and major depressive disorder. Results suggest that a supersensitive melatonin suppression to light in bipolar affective disorder (p < .005), and seasonal affective disorder (p < .05), whereas patients with major depressive disorder display similar suppression to controls. The supersensitivity may be a mechanism where by phase-delayed rhythms, are resynchronised to a new circadian position. Conversely, an abnormality may exist in the pathway from the retina to the suprachiamatic nucleus.

The effect of age and pre-light melatonin concentration on the melatonin sensitivity to dim light.

The hormone melatonin is secreted at night from the pineal gland, with light being a potent inhibitor of its secretion. Age related decreases in plasma melatonin concentrations have indicated that this may be related to pineal calcification with aging. Recently, it was shown that the melatonin sensitivity to light may be a biological marker of bipolar disorder. However, on average, patients were older than the control group in most studies, and it is not known if age has an effect on the melatonin suppression by light. To test this hypothesis, the present study investigated the effect of age on the melatonin sensitivity to dim light (200 lux). Participants were grouped into three age groups. On the testing night, they were placed in a dark room from 21.00 h to 02.30 h. Light exposure was for an hour from midnight to 01.00 h. Blood samples were collected at regular intervals for measurement of plasma melatonin. No significant differences were found in the percentage suppression of melatonin within the age groups defined in the present study (P > 0.5). No correlation was also found between age and percentage suppression of melatonin (r2 = 0.007; P > 0.1). Our results suggest that the melatonin suppression by light (200 lux) is not affected by age.

Determination of nefazodone and its pharmacologically active metabolites in human blood plasma and breast milk by high-performance liquid chromatography.

A method is described for the determination of nefazodone and its active metabolites hydroxynefazodone, the dione BMS-180492 and m-chlorophenylpiperazine in blood plasma and expressed human milk based on reversed-phase high-performance liquid chromatography. Measurements were performed on drug-free plasma and expressed human milk spiked with nefazodone and metabolites to prepare and validate standard curves and specimens collected from nursing mothers. Parent drug and metabolites were separated from the biological matrices by solid-phase extraction using CERTIFY columns. Chromatographic separation was achieved with a C18 column and compounds were detected by their absorbance at 205 nm. Trazodone was used as an internal standard. The assay was validated for each analyte in the concentration range 200 to 1200 ng/ml.

Onset of the effects of the 5-HT1A antagonist, WAY-100635, alone, and in combination with paroxetine, on olfactory bulbectomy and 8-OH-DPAT-induced changes in the rat.

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.

Effect of the menstrual cycle stage on the melatonin suppression by dim white light.

Patients with bipolar disorder have been shown to have a supersensitive melatonin suppression to dim white light (200 and 500 lux) compared to normal healthy subjects. Previous studies suggest menstrual cycle dependent changes in the melatonin rhythm, but it is not known if the melatonin sensitivity to light changes during the menstrual cycle. The present study investigated the melatonin suppression to dim white light (200 lux) in different stages of the menstrual cycle. No significant differences in the percent suppression of melatonin were found across the stages of the menstrual cycle (p = .97). Our findings suggest that the menstrual cycle hormonal changes do not affect the melatonin sensitivity to dim light in healthy controls.

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.

(+)-S-20499 -- a potential antidepressant? A behavioural and neurochemical investigation in the olfactory bulbectomised rat.

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.

Antidepressant efficacy and tolerability of the selective norepinephrine reuptake inhibitor reboxetine: a review.

Reboxetine is a unique selective norepinephrine reuptake inhibitor (NRI) with proven antidepressant efficacy in pharmacologic and biochemical tests predictive of antidepressant properties. Comprehensive clinical trials, including 8 placebo-controlled and/or active treatment-controlled studies, plus 4 open studies, have assessed the short-term and long-term efficacy and tolerability of reboxetine in patients with major depressive disorders and dysthymia. Results from a total of 690 patients who entered 5 open or placebo-controlled studies are summarized in this paper. Four hundred forty-nine patients with a diagnosis of either major depressive disorder or dysthymia were treated with reboxetine in these clinical studies of 4 weeks' to 12 months' duration. In a 6-week placebo-controlled study, clinically significant improvement (> or = 50% reduction in Hamilton Rating Scale for Depression total score) was observed at last assessment in 74% of reboxetine-treated patients compared with 20% of patients in the placebo group. Similar results were observed in the 6-week run-in phases of the 3 long-term studies, where the efficacy of reboxetine was maintained over the 12-month study period. Reboxetine was well tolerated; adverse events reported were mainly mild to moderate in severity, and there were no clinically significant changes in vital signs or laboratory parameters. The first in its class, reboxetine, a selective NRI, will provide a valuable addition to the existing armamentarium of agents used in the treatment of depression.

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.

Combining pindolol and paroxetine in an animal model of chronic antidepressant action--can early onset of action be detected?

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.