Comparison of the (pro)convulsive properties of fluvoxamine and clovoxamine with eight other antidepressants in an animal model

Freely moving rats were implanted with cortical, caudal, thalamic, and reticular electrodes. Drugs were infused intravenously at a constant rate up to a final cumulative dose of 40, 50, or 60 mg/kg. Doses of 10 mg/kg imipramine, viloxazine, desmethylimipramine, mianserin, and maprotiline produced spike-wave complexes, spikes, and increased spindling. General sustained discharges occurred after 20 mg/kg of mianserin, viloxazine, imipramine, desmethylimipramine and amitriptyline, and after 30 mg/kg of maprotiline. An abnormal high-amplitude pattern was evident after mianserin, amitriptyline, imipramine, and desmethylimipramine. On the average, seizures were observed at 40 mg/kg and were seen after desmethylimipramine (50 mg/kg), mianserin (30 mg/kg), amitriptyline (20 mg/kg), imipramine (40 mg/kg), maprotiline (40 mg/kg), and zimelidine (50 mg/kg). Ranking the tested antidepressants in decreasing order in accordance with their relative (pro)convulsive properties gives: amitriptyline greater than mianserin much greater than imipramine greater than desmethylimipramine greater than viloxazine much greater than maprotiline much greater than zimelidine greater than clovoxamine greater than nomifensine = fluvoxamine.     

Simultaneous Measurement of Various Antidepressants in the Plasma of Depressed Patients by High Performance Liquid Chromatography

Abstract: A simultaneous analytical method was reported for measuring the plasma levels of amitriptyline, imipramine, clomipramine, maprotiline, nor-triptyline, desipramine, desmethylclomipramine, desmethylmaprotiline and amoxapine by high performance liquid chromatography (HPLC). The total plasma levels of each parent drug plus its desmethyl metabolite were monitored in 29 depressed patients administered with amitriptyline, maprotiline or amoxapine using the present analytical method. There were significant linear correlations between the dose per kg body weight and the total plasma levels with amitriptyline and maprotiline, but no such correlation was found with amoxapine. The ratios of total plasma levels to dose per kg body weight of these three drugs were lower in outpatients than in inpatients. These results indicate that the monitoring of plasma levels of antidepressants is useful in treating depression.     

Simultaneous measurement of various antidepressants in the plasma of depressed patients by high performance liquid chromatography

A simultaneous analytical method was reported for measuring the plasma levels of amitriptyline, imipramine, clomipramine, maprotiline, nortriptyline, desipramine, desmethylclomipramine, desmethylmaprotiline and amoxapine by high performance liquid chromatography (HPLC). The total plasma levels of each parent drug plus its desmethyl metabolite were monitored in 29 depressed patients administered with amitriptyline, maprotiline or amoxapine using the present analytical method. There were significant linear correlations between the dose per kg body weight and the total plasma levels with amitriptyline and maprotiline, but no such correlation was found with amoxapine. The ratios of total plasma levels to dose per kg body weight of these three drugs were lower in outpatients than in inpatients. These results indicate that the monitoring of plasma levels of antidepressants is useful in treating depression.     

Comparison of the effects of maprotiline (ludiomil) and clomipramine (anafranil) on serotonin uptake and tryptophan-binding in plasma.

The influence of maprotiline or clomipramine on plasma tryptophan-binding and brain tryptophan was studied in rats. Neither compound altered tryptophan-binding nor brain tryptophan levels after acute of chronic treatment. In a comparative study maprotiline and clomipramine were administered to healthy volunteers for 4 days and the concentrations of total and free tryptophan in plasma were determined. Serotonin uptake was also measured in the platelets from these subjects. Maprotiline treatment did not inhibit serotonin uptake nor did it have any influence on plasma tryptophan binding. Clomipramine also had no influence on plasma tryptophan-binding but strongly inhibited serotonin uptake into platelets. These results confirm the earlier observation that maprotiline has no influence on serotonin uptake and can be clearly distinguished from clomipramine.     

Interactions of a non-selective monoamine oxidase inhibitor, phenelzine, with inhibitors of 5-hydroxytryptamine, dopamine or noradrenaline re-uptake

Interactions of combined antidepressants which occur in man were reproduced in rats pretreated with phenelzine, features elicited including myoclonic phenomena, an augmented lower limb flexor reflex, muscle fasiculation and fatalities, particularly with combinations incorporating 5-hydroxytryptamine (5-HT) re-uptake inhibitors. Combinations of antidepressants included phenelzine with 5-HT re-uptake inhibitors (paroxetine, fluoxetine, clomipramine); with "mixed" re-uptake inhibitors affecting 5-HT and noradrenaline (imipramine, amitriptyline); with noradrenaline re-uptake inhibitors (desipramine, maprotiline, nisoxetine) and with dopamine re-uptake inhibitors (benztropine, nomifensine). Myoclonic phenomena such as forelimb flexor-extensor movements, head and body twitches, occurred in phenelzine pretreated rats after paroxetine, fluoxetine, clomipramine, imipramine, amitriptyline and desipramine. Wet dog shakes, the most intense phenomenon, were obtained only after paroxetine, fluoxetine, clomipramine and imipramine. Myoclonic features were prevented when pretreatment included p-chlorophenylalanine but were unaffected when this incorporated alpha-methyl-p-tyyrosine; there were attenuated by methysergide, cyproheptadine, clozapine or pimozide. The myoclonic phenomena were reproduced by combination of 5-hydroxytryptophan but not L-3,4-dihydroxyphenylalanine with clomipramine. Electrocortical changes observed included 2-4 Hz, 5-8 Hz, large amplitude potentials unrelated to the myoclonic incidents and unaffected by sensory stimulation. Following phenelzine, brain monoamine oxidase (MAO) A inhibition was 99% and that of MAO B, 88%; 5-HT concentration was significantly elevated in the cortex and hypothalamus, as was hypothalamic noradrenaline. Peak and basal tensions of a lower-limb flexor reflex were elevated in phenelzine pretreated spinal rats by fluoxetine, paroxetine, clomipramine and imipramine, effects attenuated by cyproheptadine. Forelimb flexor-extensor movements and body twitches were elicited by fluoxetine and paroxetine in phenelzine pretreated spinal rats in the presence of electrical stimulation of the central stump of a divided posterior tibial nerve. Pressor responses were observed in phenelzine pretreated spinal rats given 5-HT re-uptake inhibitors, "mixed" re-uptake inhibitors and those affecting noradrenaline re-uptake; ECG anomalies occurred in such rats given clomipramine.     

Is Ro 11-2465 (Cyan-imipramine) an antagonist of postsynaptic serotonin receptors?

Summary Ro 11-2465, a selective inhibitor of serotonin uptake of the imipramine group, was examined for its central and peripheral antiserotonin activity.Ro 11-2465 (10mg/kg) antagonized the stimulation of the hind limb flexor reflex in the spinal rat evoked by serotonin agonists of direct mode of action (LSD, quipazine, m-chlorophenylpiperazine). However, in doses up to 20 mg/kg it did not inhibit the clonidine-induced stimulation of the flexor reflex. It also reduced the number of the quipazine-induced head twitches in rats (ID₅₀=20.1 mg/kg) and, in doses 0.3–10.0 mg/kg, dosedependently attenuated the pressor response to serotonin in the pithed rat. Like doxepine, amitriptyline, clomipramine and imipramine, Ro 11-2465 reduced the serotonin-induced contractions of the rat stomach fundus strip (itsIC₅₀=5×10^–5M).The obtained results indicate that like other tricyclic inihibtors of serotonin uptake, Ro 11-2465 may also weakly block the postsynaptic serotonin receptors. Additional studies with fluoxetine and Org 6582 indicate that anti-serotonin properties of tricyclic compounds are not related to the serotonin uptake blocking properties.A part of the results was presented at 7th Congress of the Polish Pharmacological Society, Pozna, September 25–28, 1980.     

Inhibitory effects of L-threo-DOPS on electroshock seizure in mice

Effects of L-threo-3,4-dihydroxyphenylserine (L-DOPS), a synthetic norepinephrine (NE) precursor, on electroshock seizure were studied in mice. All substances were administered intraperitoneally. Minimal electroshock seizure threshold (EST) was not significantly altered by L-DOPS at a dose of 200 or 400 mg/kg. L-DOPS was unable to abolish tonic extensions of hind legs in maximal electroshock seizure (MES) test at doses from 100 to 400 mg/kg. However, it significantly reduced extension/flexion (E/F) ratio in a dose-dependent manner. Furthermore, L-DOPS dose-dependently blocked maximal electroconvulsions in a combined use with nialamide (30 mg/kg), desipramine (20 mg/kg) or maprotiline (40 mg/kg) at so small doses as not to show any anticonvulsant effect when they were used alone. ED50 (with 95% confidence limit) of L-DOPS in the combination treatments were 210 (145-305), 160 (100-256) and 95 (50-181) mg/kg respectively. Those results indicate that L-DOPS has an anticonvulsant property, which is potentiated by a MAO inhibitor or NE uptake blockers. It was presumed that the effect of L-DOPS was caused by the inhibition of spreading of seizure discharges. It was suggested that L-DOPS would be a useful substance for the investigation on a role of NE in experimental epilepsy and could be used clinically as an adjunct drug for generalized tonic-clonic convulsions.     

Effects of triiodothyronine (T3) on the potentiation by antidepressants of L-5-hydroxytryptophan-induced head-twitches in mice

1. Daily injection of T3 during three consecutive days dose-dependently enhanced L-5-HTP (4 mg/kg)-induced head-twitches in mice. 2. Pretreatment with a sub-effective dose of T3 (0.06 mg/kg) markedly enhanced the ability of drugs acting mainly on noradrenergic systems (clenbuterol, desipramine, maprotiline and nomifensine) to increase the response to L-5-HTP. 3. In contrast the potentiating effects of T3 were moderate on drugs with mixed action on serotonergic and noradrenergic systems (amitriptyline, clomipramine and imipramine) and minimal on drugs acting mainly on serotonergic systems (citalopram, fluvoxamine and indalpine). 4. These data suggest that the increased responsiveness to L-5-HTP caused by T3 involves an indirect (norepinephrine-mediated) rather than a direct effect on serotonergic processes.     

Immediate effects of 14 non MAOI antidepressants in rats with spontaneous petit mal-like seizures

1. Wistar rats of a strain presenting spontaneous petit mal-like seizures were injected intraperitoneally with graded doses of 14 non-monoamine oxidase inhibitor antidepressants and the immediate effects on behavior and the EEG were recorded. 2. Amineptine and nomifensine, the two drugs interacting with dopaminergic neurotransmission, reduced the duration of spontaneous spike-wave discharges (SWD) and were thus potentially antiepileptic. 3. Trazodone increased SWD duration. 4. The antidepressants, imipramine-like (imipramine, chlorimipramine, desipramine, metapramine and amitriptyline) and non-imipraminic (minaprine, maprotiline, viloxazine, mianserin, fluvoxamine and indalpine), and the 3 noted above, had potentially convulsive effects.     

Involvement of norepinephrine neurons in the hypothermia induced by intracerebroventricular administration of 6-hydroxydopamine in mice,evidenced by antidepressants

Summary The intracerebroventricular (i.c.v.) administration of increasing doses of 6-hydroxydopamine (6OHDA) (12.5–50 g) induces in mice a dose-dependent hypothermic effect. This hypothermic effect is not affected either by serotonin uptake inhibitors (indalpine, clomipramine, trazodone, fluoxetine) or by dopamine uptake inhibitors (GBR 12783, amineptine). On the contrary, the hypothermia is partly antagonized by norepinephrine uptake inhibitors (desipramine, nomifensine, viloxazine, maprotiline, protryptiline), as well as amfonelic acid. The antagonism elicited by desipramine is observed when the drug is administered intraperitoneally (from 5 mg/kg) or intracerebroventricularly (from 5 g per mouse). 6-hydroxydopamine-induced hypothermia is antagonized by imipramine after a time lag of 1 hour; this antagonism lasts 6–11 hours after intraperitoneal administration of the drug (20 mg/kg). The hypothermic effect of 6-hydroxydopamine is diminished by a previous 6-hydroxydopamine i.c.v. administration (50 g, 7 days before), except in mice pretreated with desipramine at the time of the first 6-hydroxydopamine injection. The hypothermic effect is completely abolished by two previous 6-hydroxydopamine i.c.v. administrations (50 g, 7 days interval). It is also decreased in mice receiving DSP4 15 days before testing (50 mg/kg, i.p.). Finally, neither haloperidol (0.5 mg/kg i.p.) nor SCH 23390 (100 g/kg s.c.) antagonize 6-hydroxydopamine-induced hypothermia. It is concluded that this effect is largely depending on central norepinephrine neurons.     

Acute effects of some different antidepressant drugs on saliva composition

In a double-blind controlled cross-over trial on 20 healthy volunteers, the acute effects of single doses of amitriptyline (75 mg), zimelidine (100 mg), maprotiline (75 mg), and placebo were tested on saliva composition. From the current knowledge of the physiological regulation of the salivary glands and the different specificities of the three drugs, different responses from the salivary glands could be expected. As all three drugs have anticholinergic effects that influence the saliva secretion, the concentrations of secreted saliva components had to be recalculated with regard to changes in secretion rate. No changes in saliva composition were recorded after the intake of placebo. The most pronounced changes were observed after amitriptyline intake. Amitriptyline caused increases in the concentrations of proteins, glycoproteins, calcium and potassium. Zimelidine initially decreased the concentrations of glycoproteins and increased the concentration of calcium. Maprotiline increased the concentrations of proteins and sodium. Most of the results fit in well with the theories about facilitated serotoninergic and adrenergic transmission during treatment with antidepressants.     

Effects of zimeldine and its metabolites, clomipramine, imipramine and maprotiline in experimental allergic neuritis in Lewis rats.

The influence of the selective serotonin (5-HT) reuptake inhibiting antidepressant zimeldine and its metabolite norzimeldine was tested on experimental allergic neuritis (EAN) in Lewis rats, which is an animal model of the Guillain-Barré syndrome (GBS) in man. Zimeldine and norzimeldine both suppressed clinical signs of actively induced EAN when given at a dose of 20 mg/kg/day intraperitoneally via osmotic pumps. The effects of zimeldine, its metabolites norzimeldine and CPP 200 as well as of the antidepressants clomipramine, imipramine and maprotiline on in vitro immune response were tested. Thereby we used an immunospot assay for interferon-gamma (IFN-gamma) produced by lymph node mononuclear cells (MNC), which reflects number of memory T lymphocytes activated by antigen or lectin, in this experiment bovine peripheral nerve myelin (BPM) and phytohemagglutinin (PHA), respectively. In the IFN-gamma secretion assay zimeldine, CPP 200, clomipramine and maprotiline all in a concentration-dependent mode reduced the number of IFN-gamma secreting cells while norzimeldine and imipramine did not affect the IFN-gamma secretion. In assays for proliferation in response to antigen or lectin, the concentration 10(-4) M was judged toxic for all substances tested, and at concentrations below that all but zimeldine showed a dose-dependent slight reduction of MNC proliferation. The action of several drugs on induced T cell secretion of IFN-gamma suggests that the mechanisms for the suppressive effect of zimeldine and norzimeldine on EAN symptoms can be due to an action on myelin T cell autoreactivity. All the monoamine reuptake inhibiting antidepressants tested in this study showed immunomodulatory effects by either a reduction of the number of IFN-gamma-secreting cells or the MNC proliferation. These observations call for further studies of immunological mechanisms in the pathogenesis of mental disorders as well as on the potential role of drugs acting on the monoamine systems in the treatment of recognized autoimmune diseases.     

Neuropharmacology of the anxiolytic drug opipramol, a sigma site ligand

Although opipramol is structurally related to imipramine, it does not represent a tricyclic antidepressant drug as it does not inhibit the neuronal uptake of norepinephrine and/or serotonin. Unlike imipramine it is a rather potent sigma ligand with modest subclass selectivity which is similar in vitro as well as ex vivo. Opipramol is active in several behavioural paradigms indicative of anxiolytic properties at doses (1-10 mg/kg), which are also needed to occupy sigma binding sites. Somewhat higher doses (10-20 mg/kg) are needed for "antidepressant like" effects. The data allow the conclusion that interaction with sigma sites is involved in the anxiolytic and antidepressant effects of opipramol albeit a contribution of its weaker D (2)-antagonistic and 5-HT2-antagonistic properties cannot be totally be excluded.     

Dose-dependent down-regulation of beta-adrenergic receptors after chronic intravenous infusion of antidepressants

1. The effects of intravenous infusion of desipramine (1, 3, 10, and 60 mg/kg/day), amitriptyline, zimelidine, iprindole (3, 10, 30, 60, and 100 mg/kg/day each), imipramine (10, 30, and 100 mg/kg/day), or U-48753E (1, 3, 10, and 30 mg/kg/day) on the density of central beta-adrenergic receptors (beta-AR) were investigated in female Sprague-Dawley rats. 2. Desipramine, amitriptyline, zimelidine, iprindole, imipramine, and U-48753E dose-dependently reduced the density of beta-AR in the cerebral cortex. 3. The time of onset of down-regulation of beta-AR was negatively correlated with the doses of drugs. 4. At equipotent doses, antidepressants seem to have a similar profile for the time of onset of reduction in the density of beta-AR. 5. The results indicate that down-regulation of beta-AR may be involved in mediating the therapeutic effects of antidepressants, and this effect can be rapidly achieved by intravenous infusion of drugs.     

The effect of repeated administration of antidepressant drugs on the responsiveness of rats to catecholamine agonists

Summary The antidepressant drugs, imipramine (10mg/kg s.c.), amitriptyline (10 mg/kg s.c.), mianserin (2 mg/kg i.p.), danitracen (3 mg/kg i.p.) or the vehicle were administered to rats twice a day for 4 or 10 days. Clonidine (0.5 mg/kg s.c.) induced in rats chronically treated with the compounds studied an increase in locomotor activity but, at the same time, did not affect or decreased this activity in rats chronically treated with the vehicle or a single dose of an antidepressant. This refers, in particular, to imipramine, amitriptyline and danitracen which have a similar effect. This effect, an increase in motility, was most pronounced and common for all the three drugs (after a 4- and 10-day treatment) when clonidine was administered 72 hours after the last dose of an antidepressant. Only in a few cases the amphetamine-induced hypermotility was enhanced by a chronic administration of antidepressants (a 4-day amitriptyline treatment, 72 hours after the last injection; a 4-day mianserin or danitracen treatment, 48 hours after the last injection).The results obtained seem to suggest that a chronic administration of the antidepressant drugs may cause a change in the sensitivity of the central noradrenaline receptors.     

Chronic inhibition of the norepinephrine transporter in the brain participates in seizure sensitization to cocaine and local anesthetics

The involvement of chronic inhibition of monoamine transporters (MAT) in the brain with respect to sensitization to cocaine- and local anesthetic-induced seizures was studied in mice. Repeated administration of subconvulsive doses of meprylcaine as well as cocaine, both of which inhibit MAT, but not lidocaine, which does not inhibit MAT, increased seizure activity and produced sensitization to other local anesthetics. The effects of five daily treatments of monoamine transporter inhibitors on lidocaine-induced convulsions were examined 2 or 3 days after the last dose of the inhibitors. Daily treatments of GBR 12935, a specific inhibitor of dopamine uptake, significantly increased the incidence and the intensity of lidocaine-induced convulsions at 20 mg/kg and decreased the threshold of the convulsions. Daily treatments of desipramine and maprotiline, selective norepinephrine uptake inhibitors, markedly increased the incidence and intensity of lidocaine-induced convulsions, and decreased the threshold in a dose-dependent manner at between 5 and 20 mg/kg. Daily treatments of citalopram, a selective serotonin uptake inhibitor, at 10 and 20 mg/kg, produced no significant increase in the incidence or intensity of lidocaine-induced convulsions, but decreased the threshold of the convulsions. These results suggest that the chronic intermittent inhibition of monoamine uptake increases susceptibility to cocaine- and local anesthetic-induced seizures, and the norepinephrine transporter is an integral component of this sensitization.     

Evidence of the dual mechanisms of action of venlafaxine

BACKGROUND: Indirect evidence suggests that the antidepressant venlafaxine hydrochloride selectively inhibits serotonin (5-HT) uptake at low doses, whereas at high doses, it inhibits both 5-HT and norepinephrine (NE) uptake. We hypothesized that, in vivo, both high and low doses would inhibit the 5-HT uptake of platelets but that the higher dose would differentially blunt the pressor response to tyramine, a marker for NE uptake. METHODS: Healthy male volunteers aged 18 to 45 years received either 75 mg or 375 mg of venlafaxine hydrochloride per day, the 5-HT uptake inhibitor sertraline hydrochloride (50 mg/d), or the NE uptake inhibitor maprotiline hydrochloride (150 mg/d) (n = 8 for each of 4 treatment groups). Changes in platelet 5-HT uptake and the pressor response to intravenous tyramine were assessed following the initial dose and after 1 and 2 weeks of drug administration. RESULTS: Platelet 5-HT uptake was inhibited by venlafaxine across the dose range and by sertraline but not maprotiline. Inhibition was competitive, related to increases in affinity and not related to capacity. Steady-state drug levels were associated with a 5-HT uptake inhibition of 87% or more in subjects taking venlafaxine or sertraline. The pressor response to tyramine differentially distinguished maprotiline from sertraline and the low dose of venlafaxine but not from the high dose of venlafaxine. CONCLUSION: This study provides the first in vivo evidence in healthy humans that both 5-HT uptake and NE uptake inhibition are mechanisms of action sequentially engaged by venlafaxine over its clinically relevant dose range.     

Medication Outcome in ECT-Resistant Depression

The outcome of antidepressant treatment in 12 cases of electroconvulsive therapy (ECT)-resistant depression is presented. Eight patients had been refractory to a clinically adequate course of ECT (Hamilton Depression Scale improvement <20%) and four were partial responders (improvement 20-49%). All remitted completely on antidepressant medication within 2.2 +/- 1.1 (mean +/- SD) months of the ECT course. Remission was associated with clomipramine treatment (139 +/- 49.7 mg/day) in seven cases and maprotiline (125 mg/day) in one case. Four patients who did not respond to a tricyclic antidepressant alone remitted following supplementation (of clomipramine in 2 cases, clomipramine + haloperidol in 1 case, and imipramine in 1 case) with lithium carbonate. Although a delayed therapeutic response to ECT cannot be excluded, the results suggest that ECT may alter the sensitivity of refractory patients to antidepressant medication.     

Chronic administration of tricyclic antidepressants suppresses hypothalamo-pituitary-adrenocortical activity in male rats

The effect of chronic administration of the clinically effective antidepressants, imipramine, clomipramine and desipramine, on corticosterone (CS) release in male rats was investigated. Chronic administration of imipramine, clomipramine and desipramine at a dose of 20 mg/kg b.w./day, but not at a dose of 2 mg/kg b.w./day, suppressed blood CS concentration at 2000h and abolished its circadian rhythm. The normal circadian rhythm of CS release resumed seven days after the termination of imipramine injection. The acute administration of imipramine (20 mg/kg b.w./day) at 0800h but not at 2000h elevated CS concentrations. Chronic administration of imipramine (20 mg/kg b.w./day) tended to increase the inhibitory effect of dexamethasone on CS release. Adrenocortical sensitivity to exogenous adrenocorticotropic hormone tended to be decreased by chronic administration of imipramine (20 mg/kg b.w./day). These results indicate that antidepressants have effects on the hypothalamo-pituitary-adrenocortical axis which may confound psychoneuroendocrinological tests, such as the dexamethasone suppression test, for the diagnosis of affective disorders.     

Are the effects of the antidepressants amitriptyline, maprotiline, and fluoxetine on inhibitory avoidance state-dependent?

State-dependent learning (SDL) is a phenomenon in which the retrieval of newly acquired information is possible if the subject is in the same physiological state as during the encoding phase. SDL makes it possible to separate the effects of drugs per se on learning from the effects due to changes in drug state during the task. The present work was designed to investigate whether the antidepressants amitriptyline (30 mg/kg), maprotiline (25 mg/kg), and fluoxetine (15 mg/kg) produce SDL of the inhibitory avoidance conditioning in male and female CD1 mice. In three separate experiments, independent groups were used for each pharmacological treatment and for each sex using a 2 x 2 experimental design. The results do not show SDL in any of the drugs. In the case of amitriptilyline, the data can be attributed to a memorization deficit, while the maprotiline results are interpreted as simultaneously influenced by memorization deficit and performance facilitation due to motor impairment. Fluoxetine treatment did not produce any deteriorating effect on the conditioning. Drugs had some different effects on the performance of males and females, males showing a slightly higher deterioration than females with administration of amitriptyline and maprotiline. This study shows that these antidepressants affect the acquisition/consolidation but not the retrieval process in the inhibitory avoidance learning.