The psychopharmacological effects of repeated doses of fluvoxamine,mianserin and placebo in healthy human subjects

Summary The psychopharmacological effects of fluvoxamine, 50 mg twice a day, were compared with those of mianserin, 20 mg twice a day, and placebo, each given for 8 days in a double-blind crossover design to 9 healthy human volunteers.At least one week was left between the 8-day courses of drugs. Testing was carried out before and 3 h after taking the morning dose on Days 1 (predrug), 4, and 8, and comprised EEG, cognitive and psychomotor tasks, and self-ratings of mood and bodily symptoms.Fluvoxamine had no effect on any of the EEG wavebands, but mianserin increased voltages in the slow wavebands as compared with placebo. This effect was particularly pronounced on Days 4 and 8.Mianserin significantly decreased critical flicker fusion frequency and speed of reaction time, and slowed down tapping rate; digit symbol substitution and symbol copying test performances were also impaired by mianserin. These effects were most marked after the first dose and had lessened somewhat later in the week. Symbol copying was the only task impaired by fluvoxamine as compared with placebo.Mianserin caused drowsiness after the first dose but this effect declined by Day 8. By contrast, fluvoxamine induced feelings of anxiety, sweatiness, trembling, nausea, loss of appetite, restlessness, muscle tension, irritability, tiredness, headache, and dizziness; these effects were most evident in the middle of the week and relatively reduced at the end of the week. Mianserin produced a few of these effects but they tended to be maximal on Day 1 or 4 and then to wear off.It was concluded that fluvoxamine is much less likely to produce psychomotor and cognitive impairment on repeated usage than is mianserin, but that some adverse effects, particularly nausea, may be troublesome. Fluvoxamine would seem more appropriate in patients in whom sedation is not required, mianserin in those in whom initial sedation is acceptable.     

Effects of lorazepam on memory,attention and sedation in man: antagonism by Ro 15-1788

In this study we examined the effects of lorazepam (2.0 mg PO) plus either placebo or one of three doses of the benzodiazepine antagonist Ro 15-1788 (0.3 mg, 1.0 mg or 3.0 mg IV) on measures of memory, attention and sedation. We found that lorazepam impaired verbal secondary memory performance, but also produced subjective and objective sedation; it increased reaction time, reduced critical flicker fusion thresholds and caused subjects to make more errors on a sustained attention task and rate themselves as drowsy. Ro 15-1788 dose dependently blocked the deficit in secondary memory produced by lorazepam, but also showed monotonic dose-related antagonism of its effects on indices of sedation (with the exception of the critical flicker fusion deficit, which was unaffected). These results demonstrate that lorazepam-induced cognitive deficits can be blocked by a benzodiazepine receptor antagonist. They also suggest that the memory deficits produced in this pharmacological model of organic amnesia are not readily dissociated from deficits in attention.     

Effects of lorazepam on memory,attention and sedation in man

The effects of three doses of lorazepam (0.5, 1.0 and 2.0 mg PO) on various aspects of memory, attention and sedation are described. Lorazepam produced dose-related deficits in verbal secondary memory, choice reaction time and a novel vigilance task. It also produced a dose-dependent increase in subjective sedation, and an enhancement of visual contrast sensitivity. These results are compared with those reported earlier using the muscarinic antagonist scopolamine, and discussed in relation to models of Alzheimer's disease.     

Effects of mianserin in neuroleptic-induced parkinsonism

It has been proposed that serotonin (5-HT) antagonists counteract neuroleptic-induced extrapyramidal symptoms by disinhibition of dopamine activity. The effects of the 5-HT antagonist mianserin, the anticholinergic drug procyclidine and placebo were evaluated in 16 psychiatric patients with chronic neuroleptic-induced parkinsonism in a double-blind cross-over trial. The patients received each drug in random order in 3-week periods separated by washout periods of 2 weeks. The effect of mianserin did not significantly differ from that of placebo, while parkinsonian symptoms were significantly reduced during treatment with procyclidine (P<0.05). Although mianserin was ineffective in chronic neuroleptic-induced parkinsonism, it cannot be excluded that 5-HT antagonists may be effective in the treatment of acute extrapyramidal side effects.     

Comparative pharmacology of mianserin,its main metabolites and 6-azamianserin

Summary Mianserin, its main metabolites (8-hydroxymianserin, desmethylmianserin and mianserin-N-oxide) and a mianserin analogue, 6-azamianserin (ORG 3770), were compared with regard to effects on monoamine uptake systems, -adrenoceptors, rat exploratory activity and rat muricidal behaviour. Mianserin and desmethylmianserin inhibited noradrenaline uptake into synaptosomes (IC50's 30 and 60 nM, respectively) whereas the other compounds were much less active. Synaptosomal serotonin uptake was only inhibited to a small extent by desmethylmianserin (IC50 6 M) and 8-hydroxymianserin (IC50 9 M). Dopamine uptake was not affected by any of the compounds tested. All compounds except mianserin-N-oxide blocked presynaptic -receptors as shown by the potentiation of high-K-induced release of noradrenaline from rat cerebral cortex slices. For mianserin and 6-azamianserin this blockade was shown to be stereoselective. Desmethylmianserin was less potent than mianserin. Binding of ³H-dihydroergocryptine to rat cerebral cortex membranes was inhibited by all compounds except mianserin-N-oxide. Again, desmethylmianserin was less active than mianserin. None of the compounds appeared to block presynaptic -receptors in preference to postsynaptic -adrenoceptors. This was confirmed by the fact that the compounds studied failed to antagonize clonidine-induced sedation in the open field. Clonidine-induced diuresis, however, was stereoselectively inhibited by 6-azamianserin, but the involvement of 2-receptors in this phenomenon is not firmly established.Antihistamine properties as determined by ³H-mepyramine binding to rat brain membranes were most pronounced for 6-azamianserin. Mianserin was slightly less potent and desmethylmianserin and 8-hydroxymianserin were 10 and 30 times less potent than mianserin, respectively.Muricidal behaviour was inhibited by all compounds except mianserin-N-oxide. The least active was 8-hydroxymianserin. In contrast to mianserin and desmethylmianserin, the blockade of muricidal behaviour by 6-azamianserin was non-specific since it occurred at doses which caused a strong depression of rat open field behaviour. Mianserin was less sedative than 6-azamianserin whereas the metabolites showed no sedative effects at doses up to 32 mg/kg in the open field.It is concluded that the main metabolites of mianserin possess pharmacological properties which may add to the therapeutic potential of mianserin. Clinical testing of 8-hydroxymianserin and 6-azamianserin may give an answer to the question whether the antidepressant effect of mianserin is solely based upon its interaction with presynaptic -adrenoceptors or is due to a concomitant blockade of noradrenaline reuptake.     

Effects of tianeptine and mianserin on car driving skills

RATIONALE: Tianeptine is a novel antidepressant which enhances the reuptake of serotonin (5-HT). Previous studies suggest that tianeptine has a non-sedative side-effect profile, but its effects on everyday activities including car driving have not been fully explored. OBJECTIVES: To assess the effects of tianeptine on tests related to car driving performance. METHOD: Sixteen healthy volunteers received acute doses of tianeptine 12.5 mg and 37.5 mg, mianserin 30 mg and placebo in a double blind four-way crossover study. The effects of treatment on self assessed ratings of sedation (LARS), two valid and reliable laboratory performance measures, critical flicker fusion (CFF) and choice reaction time (CRT) and an "on-the-road" measure of one aspect of car driving performance, brake reaction time (BRT) were examined. The BRT test was administered at baseline and at 1.5, 3, 4.5 and 6 h post-dose, while LARS, CFF and CRT were administered at baseline and at 1, 2, 4 and 5 h post-dose. For all data, the maximum change from baseline was calculated and used in the analysis. RESULTS: Tianeptine had no measurable effect on performance, compared to placebo, on any of the variables investigated. Compared to placebo, mianserin was shown to lower CFF thresholds (P = 0.01), increase reaction times on both the CRT (P = 0.001) and the BRT (P = 0.01) tests and was subjectively rated as more sedative than placebo (P = 0.01). CONCLUSION: The apparent lack of counter-therapeutic side-effects produced by an acute dose of tianeptine suggest that it may be a suitable antidepressant for use in an ambulant population.     

Pharmacokinetics of fluvoxamine maleate after increasing single oral doses in healthy subjects

The pharmacokinetics of fluvoxamine after single oral administration of 25, 50, and 100 mg fluvoxamine maleate was studied in a three-way cross-over study in 12 healthy male subjects. Fluvoxamine was administered orally in a solution. For doseproportionality, AUC, and C_max-dose relationships were evaluated by linear regression. Plasma concentrations increased in a linear dose-dependent manner in the dose range between 25 and 100 mg; t_1/2 and T_max showed no significant differences among treatments. Fluvoxamine was well tolerated.     

Influence of age on mianserin pharmacokinetics

The pharmacokinetics of Mianserin (MIA) after acute administration have been studied in nine volunteers, divided into two groups according to age. The subjects were given a single oral dose of 30 mg MIA. The plasma peak time was shorter in the younger subjects than in the older. In general, the concentrations of MIA in the plasma were higher in the older subjects than in the younger, and, in the former group there was no relationship between administered dose (mg/kg) and plasma levles. The area under curve, volume of distribution and clearance were significantly different in the two groups. The side effects (both incidence and type) differed in the two groups There were no significant changes in blood pressure, either supine or standing. The sedative effect was more marked in the young than in the elderly subjects. A relationship between drowsiness and MIA plasma levels was observed only in the younger subjects.     

Benzodiazepines,memory and mood: a review

The amnestic effects of benzodiazepines (BZs) have attracted considerable research interest. This reflects not only the clinical implications of memory failure for people prescribed these drugs but also the potential of BZs as tools in modelling organic memory problems. As well as impairing certain aspects of human memory functions, BZs affect mood states by reducing anxiety and inducing sedation. An unresolved issue is the extent to which the amnestic effects of BZs are separable from their sedative and anxiolytic effects. The present review focusses on this issue, first presenting a conceptual framework for evaluating the interrelationship between the various effects of BZs, and then summarising recent volunteer and patient research relevant to dissociating amnestic from other effects. Clinical implications are discussed in terms of the use of BZs alone or as adjuncts to psychotherapy for anxiety disorders, and attention is drawn to the need for more ecological validity in psychopharmacological research. Theoretical implications are explored in terms of BZs as tools in studying both memory failure and the relationship between mood and cognition.     

Sedative,memory, and performance effects of hypnotics

The sedative, amnestic, and performance disruptive effects of benzodiazepine (Bz) receptor selective and non-selective hypnotics were studied in 23 healthy, normal subjects, aged 26.8±1.0 years. Triazolam (0.25 and 0.50 mg), zolpidem (10 and 20 mg) and placebo were administered, double-blind, at bedtime in a repeated measures design. During an awakening 90 min later (at approximate peak concentration of each drug) a 30-min performance battery which included memory, vigilance, and psychomotor tasks was completed. Each drug and dose impaired memory (both immediate and delayed), vigilance, and psychomotor performance relative to placebo. Among active drugs impairment was greatest with zolpidem 20 mg, next triazolam 0.50 mg, then zolpidem 10 mg, and finally triazolam 0.25 mg. Next morning delayed recall was also impaired by all drugs and doses (i.e. anterograde amnesia). The amnestic and performance-disruptive effects paralleled the relative hypnotic effects of the drugs and doses. No receptor selectivity in these pharmacodynamic effects was observed.     

Psychopharmacological treatment of social phobia; a double blind placebo controlled study with fluvoxamine

Previous studies have shown selective and non-selective monoamine oxidase inhibitors (MAOIs) to be effective in the treatment of social phobia. In this study we investigated the efficacy of selective serotonin reuptake inhibitors (SSRIs) in social phobia. Thirty patients with social phobia (DSM-IIIR) were treated with the SSRI fluvoxamine (150 mg daily) using a 12-week double-blind placebo controlled design. A substantial improvement was observed in seven (46%) patients on fluvoxamine and in one (7%) on placebo. Statistically significant effects were seen on measures of social anxiety and general (or anticipatory) anxiety in patients treated with fluvoxamine compared with placebo. The level of phobic avoidance decreased also but the difference at endpoint between fluvoxamine and placebo failed to reach statistical significance. It is concluded that treatment with the SSRI fluvoxamine has beneficial effects in patients suffering from social phobia, suggesting that serotonergic mechanisms might be implicated in social anxiety.     

Models of memory dysfunction? A comparison of the effects of scopolamine and lorazepam on memory,psychomotor performance and mood

The effects on memory, psychomotor functions and mood of intramuscular scopolamine (0.3 mg, 0.6 mg) were compared with those of oral lorazepam (2 mg) and placebo. Thirty-six volunteers took part in a doubleblind, independent groups design. Subjects completed a battery of tests 1 and 3 h after drug administration. Both doses of scopolamine produced levels of sedation comparable to that produced by lorazepam. The time course of effects of scopolamine and lorazepam differed but the pattern of psychomotor impairments and amnestic effects produced was very similar. In terms of mood, lorazepam had an anxiolytic effect whereas scopolamine increased ratings of anxiety. Levels of sedation, indexed by either subjective ratings or motor retardation (tapping speed), were related more to psychomotor performance than to performance on memory tasks. The results suggest that benzodiazepines and scopolamine have similar amnestic and sedative effects and as such may not offer distinct models of memory dysfunction.     

Dissociation of benzodiazepine-induced amnesia from sedation by flumazenil pretreatment

The human amnestic syndrome associated with lesions of the hippocampus and amygdala is characterized by a selective impairment of recent (explicit, episodic) memory. Benzodiazepine (BZ) treated normal subjects demonstrate similar, marked impairments in episodic memory, but in addition, BZ also induces sedation and inattention. Thus, the amnestic effects of BZ may be secondary to drug-induced sedation. However, when subjects were pretreated with the specific BZ receptor antagonist, flumazenil, the sedative and attentional effects of diazepam were blocked, but a marked impairment in episodic memory still occurred. This demonstrates that, using neuropharmacological methods, it is possible to produce a dissociation of memory impairment from inattention and sedation. Such distinct patterns of cognitive dysfunction may serve as models for clinical cognitive syndromes.A preliminary version of these findings were presented at the American College of Neuropsychopharmacology Annual Meeting in Washington, DC., December 1986     

Effect of fluvoxamine on the pharmacokinetics of quinidine

Objective: To investigate the possible involvement of cytochromes CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine. Methods: This was an open study of six healthy young male volunteers. The pharmacokinetics of a 200-mg single oral dose of quinidine were studied before and during daily treatment with 100 mg fluvoxamine. Biomarkers of other isozyme activities in the form of caffeine, sparteine, mephenytoin, tolbutamide and cortisol metabolism were applied. Results: The results showed a statistically significant median reduction of 29–44% in the quinidine total apparent oral clearance, partial clearances by 3-hydroxylation and N-oxidation and residual clearance during fluvoxamine treatment. Renal clearance was unaffected by fluvoxamine. Conclusions: The effect of fluvoxamine on the formation clearances of 3-hydroxyquinidine and quinidine-N-oxide most likely reflects inhibition of cytochrome P ₄₅₀3A4 by fluvoxamine at clinically relevant doses. The results of this study do not rule out a possible involvement of CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine. Received: 16 December 1998 / Accepted in revised form: 5 March 1999     

Bioavailability of fluvoxamine given with and without food

The influence of concomitant food intake on plasma concentrations of the antidepressant drug fluvoxamine maleate was investigated in a two-way, crossover study design. Eight male and four female healthy, young volunteers received a single oral dose of fluvoxamine maleate (50 mg, tablet) on two occasions: after an overnight fast and immediately after a breakfast. Food did not affect maximum fluvoxamine plasma levels (C_max), or the time to reach C_max (t_max). The plasma AUC of fluvoxamine was on average 7 per cent lower in the fed than in the fasted state. It is concluded that the effect of food on the pharmacokinetics of fluvoxamine is negligible.     

Self-rated sedation and plasma concentrations of desmethyldiazepam following single doses of clorazepate

Plasma concentrations of desmethyldiazepam (DMDZ) and intensity of self-rated sedation (SRS) were measured at multiple points in time during 6h after a single 15 mg oral dose of clorazepate dipotassium. Mean plasma DMDZ levels and mean SRS scores both became maximal at 1.0–2.5 h after drug dosage. By 6 h, however, mean SRS had returned to the predrug baseline score while mean DMDZ concentration fell only slighty from the maximum value. Disappearance of SRS despite persistence of high DMDZ levels might be due to adaptation or tolerance. If this is the case, subjective effects of benzodiazepines may depend upon duration of drug exposure as well as dose and concentration.     

Effects of chronic lithium, amitriptyline and mianserin on glucoregulation, corticosterone and energy balance in the rat

Major negative side-effects reported for mood-stabilizing and antidepressant drugs in humans are excess weight gain and carbohydrate craving. The aim of the present study was to establish whether the rat could usefully be employed in investigation of these phenomena. Three experiments investigated the effects of chronic lithium (40 mg/kg LiCl), amitriptyline (2.5 mg/kg), mianserin (2.5 mg/kg) and saline administration (15-20 days, one subcutaneous injection/day) on body weight, food intake and fluid intake. Water and food cubes were provided in all experiments. Additionally available, as separate fluid sources, in Experiment 2 were 24% sucrose and 0.6% saccharin and in Experiment 3, 0.6% saccharin. Blood was collected for plasma glucose and insulin determinations 20-24 hours after the final injections. Lithium administration resulted in a marked increase in weight gain but only if both sucrose and saccharin were available (Experiment 2). Saccharin intake was increased with lithium treatment as was total caloric intake with sucrose available. Amitriptyline induced a sweetness craving; however, weight gain was somewhat depressed with just cubes available (Experiment 1) and only normalised by the additional availability of sucrose and saccharin (Experiment 2). With amitriptyline, total caloric intake was never different from controls. Weight gain was slightly suppressed and caloric intake slightly elevated by mianserin but importantly the two effects combined for a decrease in metabolic efficiency which was particularly exaggerated under the condition of carbohydrate availability (Experiment 2). Lithium and amitriptyline both produced hyperinsulinemia with normoglycemia whether or not the rate of weight gain was changed and whether or not intake was increased. Corticosterone levels were elevated by all drug treatments in Experiment 1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of fluvoxamine treatment on cognitive functioning in the alcoholic Korsakoff syndrome

Eight patients suffering from the alcoholic Korsakoff syndrome (AKS) were entered in a double-blind cross-over trial of fluvoxamine 200 mg per day for 4 weeks versus matched placebo for 4 weeks. At the end of each phase, patients were assessed using a detailed neuropsychological test battery. Verbal fluency performance was significantly impaired following fluvoxamine treatment. No significant differences emerged on any of the other cognitive test measures when fluvoxamine was compared with placebo. However, two of the patients developed a major depressive episode while receiving fluvoxamine.     

Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin

In order to evaluate serotonin (5-HT) function in panic disorder, a double blind placebo controlled study was conducted with ritanserin, a specific 5-HT₂ receptor antagonist, and fluvoxamine, a selective 5-HT reuptake inhibitor, in 60 patients with panic disorder. Patients were treated for 8 weeks with 150 mg fluvoxamine, 20 mg ritanserin or placebo; these dose levels were reached after 1 week. In addition, as an index of 5-HT function in panic disorder, plasma concentration of -endorphin, cortisol and 5-hydroxyindolacetic-acid (5-HIAA) were measured. Furthermore, 5-HT uptake in blood platelets was assessed. Noradrenergic function was assessed by measuring plasma MHPG concentration. In addition, plasma melatonin concentration was measured. Treatment with fluvoxamine resulted in a profound reduction in the number of panic attacks, followed by a decrease in avoidance behavior. Treatment with ritanserin appeared to be ineffective. During treatment no significant changes were observed in plasma concentrations of -endorphin, cortisol, 5-HIAA and MHPG. With respect to 5-HT kinetics in blood platelets, a substantial increase in K_m was observed after treatment with fluvoxamine, whereas V_max decreased. After treatment with fluvoxamine, plasma concentration of melatonin was significantly increased, which suggests that melatonin synthesis is in part under serotonergic control. The findings of the present study do not support the hypothesis that 5-HT₂ receptors are supersensitive in patients suffering from panic disorder, but allow no conclusions about the involvement of other 5-HT receptor subtypes.     

Acute and chronic effects of the atypical antidepressant,mianserin on brain noradrenergic neurons

Corticotropin-releasing factor (CRF), which may serve as a neurotransmitter in the noradrenergic nucleus, locus coeruleus (LC), has been postulated to be hypersecreted in depression. The present study was designed to test the hypothesis that antidepressants interfere with CRF putative neurotransmission in the LC. The acute and chronic effects of the atypical antidepressant mianserin on LC spontaneous discharge, LC sensory-evoked discharge, LC activation by a stressor which requires endogenous CRF, and LC activation by ICV CRF were characterized in halothane-anesthetized rats. Acute IV administration of mianserin (0.0001–1.0 mg/kg) increased LC spontaneous discharge and decreased LC discharge evoked by repeated sciatic nerve stimulation in a dose-dependent manner. Additionally, mianserin (0.1 mg/kg) inhibited LC activation by hemodynamic stress (IV infusion of nitroprusside) and by ICV administration of CRF (3.0 µg). In rats chronically administered mianserin LC spontaneous and sensory-evoked discharge rates, and LC activation by CRF were similar to those of untreated rats or rats chronically administered saline. Moreover, acute IV administration of mianserin (0.1 mg/kg) to rats chronically treated with mianserin was less effective in altering LC spontaneous and sensory-evoked discharge. In contrast, LC activation by hemodynamic stress was still greatly attenuated in rats chronically administered mianserin. This is similar to the previously reported effect produced by chronic administration of the antidepressant, desmethylimipramine. The present results demonstrate that acute administration of low doses of mianserin attenuates LC activation by a variety of stimuli and suggest that tolerance developes with chronic administration to some of the effects of mianserin on LC discharge characteristics. The finding that LC activation by hemodynamic stress, which requires endogenous CRF, is attenuated after chronic mianserin administration suggests that interference with putative CRF neurotransmission in the LC may be an important common mode of antidepressant action.This work was supported by U.S.P.H.S. Grants MH42796, MH40008, MH00840, and a NARSAD award to A.L.C.