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.     

Tricyclic antidepressants, thyroid function, and their relationship with the behavioral responses in rats

We first studied the effects of tricyclic antidepressants (TCAs) on thyroid function in rats in the learned helplessness paradigm. TCAs (clomipramine 32 mg/kg, desipramine 16, 24 mg/kg, or imipramine 8, 16, 32 mg/kg per day) were injected IP for 5 consecutive days. Blood samples were collected 1 hr after the last administration of the antidepressant for radioimmunoassay determination of triiodothyronine (T3) and thyrotropin. Whereas inducing helplessness did not result in any change in T3 and thyroid-stimulating hormone (TSH) levels, TCA therapy dose dependently decreased the T3 levels without changing TSH levels in helpless animals and in naive control rats. To further the investigation, the effects of TCAs on thyroid function were examined using two models of experimentation, one involving diabetes induction, the other using food deprivation; both are known to induce a resistance to TCAs that is reversible under T3 treatment. In both models, a decreased T3 level existed prior to the TCA administration. Although they had no effect on behavior, TCAs further decreased the T3 levels in diabetic and food-restricted rats. This study confirms that TCAs decrease thyroid function and suggests that the antidepressant effect of TCAs is not related to their T3 decreasing effects.     

Cardiovascular and anticholinergic effects of zimelidine

1. Pentobarbital anaesthetized mongrel dogs on artificial respiration were instrumented for recording of cardiovascular parameters. 2. Zimelidine or tricyclic antidepressants (amitriptyline, clomipramine or desipramine) were given i.v. at a rate of 0.5 mg/kg/min. 3. Zimelidine caused a moderate decrease in mean arterial blood pressure and in peripheral resistance. These effects were not dose dependent. 4. The tricyclic antidepressants induced a dose dependent decrease in mean arterial blood pressure and dose dependent increases in left ventricular enddiastolic pressure and in right atrial pressure. 5. It is concluded that the tricyclics have direct effects on the heart. Zimelidine has negligible direct heart effects but decreases peripheral resistance. 6. Studies in rat brain homogenates indicated very low affinity of zimelidine to muscarinic receptors. 7. Studies in mice indicated no central or peripheral anticholinergic effects of zimelidine in contrast to the tricyclics.     

Antidepressant drugs and ethanol: Behavioral and pharmacokinetic interactions in mice

Summary The interactions between ethanol and antidepressant drugs (both tricyclics and newer non-tricyclics) were studied in mice. The ability of these drugs to enhance the sedative effects of ethanol at two different doses (3.2 and 4.0 g/kg) was measured. The percentage of mice losing the righting-reflex was used for the lower dose, and the duration of ethanol-induced sleep was used at the higher dose. The relative order of potency was amitriptyline>-imipramine>maprotiline=mianserin>desipramine>-chlorimipramine>iprindole>-alaproclate>norzimelidine>-zimelidine. Amitriptyline (60 mg/kg) caused death in all mice when combined with 4.0 g/kg ethanol. Clinically established antidepressants which enhanced ethanol sedation only at doses considerably above therapeutic levels were zimelidine and iprindole. The relative potency of the antidepressants to enhance ethanol sedation is correlated with their inherent sedative properties which are in turn related to their ability to block central 5-HT,-NA, muscarinic and H₁-receptors. Amitriptyline (20 mg/kg) was found to increase ethanol plasma levels to 202, 167 and 132% of control values at 30, 60 and 90 min after ethanol administration, respectively. Desipramine, mianserin and alaproclate also increased ethanol plasma levels initially, but to a lesser extent. These findings suggest that in addition to their sedative effect, several antidepressants, particularly amitriptyline, are likely to interact with ethanol by increasing its concentration in plasma.     

Prolactin secretion in posterior pituitary lobectomized rats: differential effects of 5-hydroxytryptophan and ether

The objective of this study was to determine whether the posterior pituitary mediates the prolactin (PRL) releasing activities of serotonin and ether. Ovariectomized (OVEX) rats were subjected to posterior pituitary lobectomy (LOBEX) or sham surgery (SHAM). Either 1 or 12 days after surgery, rats were injected i.v. with 20 mg/kg b. wt. of 5-hydroxytryptophan (5-HTP), which is a precursor of serotonin. A second group of rats was exposed to ether vapors for 10 min. Blood was collected from a jugular cannula before and after the treatments and analyzed for PRL. On either 1 or 12 days after surgery, injection of 5-HTP increased plasma PRL levels 5–10 fold in both LOBEX and SHAM rats. This was followed by a decline to preinjection levels within 60–90 min. LOBEX and SHAM male rats which were injected i.p. with 50 mg/kg b. wt. of 5-HTP, also showed marked and similar elevations of plasma PRL levels 12 days after surgery. Exposure of OVEX rats to ether elicited a 2–3 fold rise in plasma PRL levels only on day 1, but not on day 12, after LOBEX. The ether-induced rise in PRL was similar in SHAM rats tested on both days. These results indicate that the 5-HTP-induced rise in plasma PRL levels is independent of the posterior pituitary, regardless of the sex, the route of drug administration or the length of time after surgery. In contrast, the PRL response to ether stress is diminished within 12 days after LOBEX. The evidence that the PRL responses to 5-HTP and to ether might be mediated via different neuronal mechanisms is discussed.     

Involvement of 5-HT2 receptors in the LSD- and L-5-HTP-induced suppression of lordotic behavior in the female rat

Summary Copulatory behavior in the ovariectomized rat, the lordotic response (L. R.), was induced by estrogen followed by progesterone. L. R. is inhibited by lysergic acid diethylamide (LSD) (0.05 mg/kg) and by Levo-5-hydroxytryptophan (L-5-HTP) (2.5 mg/kg). The effects of the putative 5-HT antagonists lisuride, metergoline, methysergide, mianserin, cinanserin, cyproheptadine, pirenperone and altanserin on the LSD-induced inhibition of L. R. were tested. Lisuride, metergoline, methysergide and mianserin were found to have no LSD-blocking effect. In contrast, cinanserin, cyproheptadine and pirenperone acted antagonistically to LSD, within a critical dose range. The selective 5-hydroxytryptamine₂ (5-HT₂) receptor antagonist altanserin effectively prevented the LSD-induced inhibition of L. R., and the doses required (0.05–0.20 mg/kg) indicated a comparatively high antagonistic potency. In addition altanserin (0.2 mg/kg) effectively prevented the lordosis inhibitory effect induced by L-5-HTP (2.5 mg/kg), after pretreatment with pargyline and RO4-4602. It is suggested that the suppression of copulatory behavior caused by LSD and L-5-HTP is mediated by 5-HT₂ receptors.     

Effects of mianserin on human sleep

Sleep EEG and nocturnal penile tumescence (NPT) were investigated in 6 healthy men during placebo and mianserin administration and after mianserin withdrawal. The results were assessed in a historical comparison with those previously obtained with clomipramine. With mianserin, REM sleep was suppressed slightly. However, the suppressive effect of mianserin on REM sleep--based on the historical comparison--was significantly weaker than that of clomipramine throughout all the drug nights. Accordingly, a rebound increase in REM sleep was not observed after withdrawal. Less suppressive effects on NPT and disturbance of sexual function with mianserin than with clomipramine were observed. We suggest that a correlation between the prolonging effect on REM latency and the clinical antidepressant effect is limited to some antidepressants.     

Sildenafil, a phosphodiesterase type 5 inhibitor, enhances the activity of two atypical antidepressant drugs, mianserin and tianeptine, in the forced swim test in mice

Sildenafil, a selective phosphodiesterase type 5 inhibitor, has recently been reported to abolish anti-immobility action of antidepressant drugs, i.e., bupropion, venlafaxine and S-citalopram, in the forced swim test in mice. The present study was designed to investigate the influence of sildenafil on the potential of two atypical antidepressants, namely mianserin and tianeptine. Swim sessions were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of the behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was measured with photoresistor actimeters. To evaluate the potential pharmocokinetic interaction, total brain concentrations of the studied antidepressants were determined by HPLC method. Sildenafil at a dose of 2.5 mg/kg did not affect the activity of mianserin (20 mg/kg) in the forced swim test. Interestingly, at higher doses (5 and 10 mg/kg), sildenafil significantly enhanced the anti-immobility action of mianserin. Likewise, sildenafil (5, 10 and 20 mg/kg) robustly augmented the antidepressant activity of tianeptine (30 mg/kg). Mianserin alone, as well as in a combination with sildenafil at the highest dose, caused a potent reduction in locomotor activity. However, the changes in motor activity did not interfere with the data obtained in the forced swim test. Sildenafil significantly increased the total brain tianeptine concentration. No alteration in mianserin level in the brain after sildenafil co-administration was observed. The present study suggests that sildenafil enhances the activity of mianserin and tianeptine in the forced swim test in mice. The changes in the antidepressant activity of mianserin evoked by sildenafil co-administration were related to pharmacodynamic interaction while the interaction between tianeptine and sildenafil was, at least in part, pharmacokinetic in nature.     

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.     

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.     

Blockade of a 5-hydroxytryptophan-induced animal model of depression with a potent and selective 5-HT2 receptor antagonist (LY53857)

To test the hypothesis that a new potent and selective 5-HT2 receptor antagonist would be an excellent blocker of D,L-5-hydroxytryptophan (5-HTP)-induced response suppression in an animal model of depression, we administered LY53857 60 min prior to 5-HTP injections into rats working on an operant schedule for milk reinforcement. As predicted, LY53857 pretreatment significantly blocked 5-HTP depression (90%) in doses as low as 0.1 mg/kg ip. When the dose of LY58357 was further reduced to 0.025 mg/kg, blockade of 5-HTP-induced depression was still greater than 30%. In doses as high as 5.0 mg/kg, LY53857 alone had no effect on the baseline performance of rats working a VI 1 schedule. Pretreatment with desipramine (2.5 mg/kg), an antidepressant characterized as having major noradrenergic effects, did not significantly block the 5-HTP-induced depression. These data suggest that the 5-HTP-induced depression is mediated by serotonergic mechanisms involving 5-HT2 receptors, as LY53857 is a selective antagonist of these receptors. These data also support the suggestion, based on other published data from this laboratory, that some antidepressants are antagonizing 5-HT2 receptors in our animal model of depression and may also act in a similar manner in depressed patients. Thus, this new drug could be of interest as a possible antidepressant agent of the general type that was proposed earlier by Aprison and Hingtgen (1981).     

Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular dopamine in the frontal cortex of freely moving rats

NMDA receptors play a role in the aetiology of depression with non-competitive NMDA receptor antagonists such as amantadine showing synergy with conventional antidepressants. To advance a neurochemical rational for these findings, we have studied the effects of administration of amantadine and budipine with the antidepressants reboxetine (REB), paroxetine (PAROX) and clomipramine (CLOM) on extracellular DA in rats using microdialysis. Acutely, amantadine (40 mg/kg) or budipine (10 mg/kg) did not significantly alter extracellular DA. REB (10 mg/kg), PAROX (10 mg/kg) both increased cortical DA while CLOM (10 mg/kg) produced a decrease. When amantadine or budipine was administered 30 min before the antidepressants, DA increases were markedly greater than following the antidepressants alone. Chronically drug effects were studied at 4, 7, 14 and 21 days. Amantadine and budipine did not significantly alter extracellular DA at any time. The three antidepressants elicited a gradual increase in DA which became significant after 7 days and tended to plateau thereafter. When amantadine (20 mg/kg) or budipine (5 mg/kg) was co-administered with the three antidepressants, two differences were seen compared with the antidepressants alone. Firstly, the time required for significant increases in cortical DA was reduced with elevated levels now being observed by 4 days. Secondly, the increase in extracellular DA was greater in these rats throughout the experiment. If increased extracellular DA represents a step in the mechanism of action of antidepressants, these data suggest that combined treatment with clinically tolerated NMDA antagonists such as amantadine could reduce the delay in therapeutic onset of antidepressants and possibly enhance their efficacy.     

Are gender differences important for the clinical effects of antidepressants?

OBJECTIVE: Gender differences in antidepressant treatment response, side effects, dropout rates, and plasma concentrations were examined in patients with major and predominantly melancholic depression. METHOD: The study included a subgroup of 292 inpatients (96 men, 196 women) from three Danish double-blind, randomized, controlled trials. All patients completed a 5-week treatment period and fulfilled the DSM-III or DSM-III-R criteria for major depression. Clomipramine (150 mg/day) was the reference treatment, and comparable treatments were citalopram (40 mg/day), paroxetine (30 mg/day), and moclobemide (400 mg/day). Assessments were performed by using the 17-item Hamilton Depression Rating Scale and the Udvalg for Kliniske Unders?gelser Side Effect Rating Scale. In a subgroup of 110 patients, weekly measurements of clomipramine plasma concentrations were obtained. Nonparametric statistical tests and multiple linear and logistic regression models were used for statistical evaluations. RESULTS: Both genders had similar remission rates (Hamilton depression scale score <8) when treated with clomipramine and had significantly higher remission rates with clomipramine than with the comparable treatments. The plasma concentrations of clomipramine were significantly higher for female than for male patients. No gender differences were found in posttreatment Hamilton depression scale scores, nor did the therapeutic effects of treatment depend on gender. Rates of dropout and side effects were similar for men and women. No relationship between plasma concentrations, gender, and therapeutic outcome was found. CONCLUSIONS: In a group of patients with major and predominantly melancholic depression, differentiation according to gender was not important in treatment with common antidepressants. Women appeared to have higher plasma concentrations of tricyclic antidepressants than men. The consequences of this difference for clinical effects are unclear. Gender-specific recommendations for dosing of tricyclic antidepressants may be considered.     

Effect of serotonergic agents on regional concentrations of somatostatin- and neuropeptide Y-like immunoreactivities in rat brain.

A possible role for neuropeptides in affective disorders is suggested by many investigators. Somatostatin-like immunoreactivity (SS-LI) and neuropeptide Y-like immunoreactivity (NPY-LI) concentrations are demonstrated to be reduced in cerebrospinal fluid from depressed patients. We have shown that long-term treatment with serotonin uptake inhibitors, clomipramine and zimelidine, reduce brain SS-LI concentrations in the rat. We have studied the effect of serotonergic agents on regional brain SS-LI and NPY-LI concentrations in rats. Long-term treatment with 5-hydroxytryptamine (5-HTP), a serotonin precursor, caused reductions in SS- and NPY-LI levels in the hypothalamus. SS- and NPY-LI concentrations in the brain were markedly elevated by treatment with p-chlorophenylalanine, a serotonin synthesis inhibitor. Intracerebroventricular administration of 5,7-dihydroxytryptamine, a serotonin neurotoxin, resulted in elevations of both peptides in the brain. These results suggest a inhibitory role for the serotonergic system in the brain in the regulation of SS and NPY.     

Acute effects of zimelidine and alaproclate, two inhibitors of serotonin uptake, on neuroendocrine function.

The accumulation of 14C-5-hydroxytryptamine in human platelets in vitro and plasma levels of a number of hypophyseal hormones and cortisol in healthy male volunteers were determined after acute oral administration of zimelidine and alaproclate, two selective inhibitors of serotonin (5-HT) uptake. Alaproclate (100 mg) significantly inhibited the accumulation of 14C-5-HT by 42% at 90 minutes but showed no significant effect at 4 hours. At 200 mg the decrease in the accumulation was 55% after 90 minutes and 31% after 4 hours. Zimelidine (200 mg) caused a 72% decrease at 90 minutes and 73% at 4 hours. Plasma levels of prolactin, growth hormone, luteinizing hormone, follicle stimulating hormone, and thyroid stimulating hormone remained unchanged after zimelidine and alaproclate, and the levels were comparable to those after placebo. A physiological decline of plasma cortisol levels was noted in the morning during the test period of 4 hours, but there were slight differences in the secretory pattern after the different drugs used.     

The role of serotonin (5-HT) in the control of TSH and prolactin release in euthyroid subjects as assessed by the administration of ketanserin (5-HT2 antagonist) and zimelidine (5-HT re-uptake inhibitor)

We have studied the effects of ketanserin, a specific 5-HT2 antagonist, and zimelidine, a selective inhibitor of 5-HT re-uptake into central nervous system presynaptic terminals, upon basal and TRH stimulated serum TSH and prolactin levels in euthyroid individuals. Ten normal volunteers were studied (five male and five female), each receiving oral ketanserin and oral zimelidine during respective seven day periods, separated by an interval of at least two weeks. A standard TRH test (200 micrograms i.v.) was carried out before and after each period of drug administration, serum samples being obtained for TSH and prolactin estimation. We were unable to demonstrate any modification of basal or TRH-stimulated TSH and prolactin levels by the oral administration of either ketanserin or zimelidine, suggesting that 5-HT has no significant role in the physiological release of either TSH or prolactin.     

Measurement of basal plasma levels of 3 anterior pituitary hormones during acute or chronic treatment with tricyclic antidepressants

Prolactin, growth hormone and thyrotropin plasma levels have been evaluated in depressive in-patients, either during the first day of clomipramine or amitriptyline treatment, or after their chronic administration. Prolactin levels temporary rise during the first day of clomipramine or amitriptyline treatment in 6 patients out of 11, with a lag in relation to the drug plasma peak. A significant increase is observed after a 28 days treatment with clomipramine and a non significant decrease, after a 28 days treatment with amitriptyline. As for human growth hormone, a rise is found in 5 out of 8 clomipramine treated subjects but neither any variation with amitriptyline nor any significant variation with chronic administration of both drugs occur. Finally, thyrotropin plasma levels display no variation after acute or prolonged treatment with clomipramine or amitriptyline. These results are compared with those of literature, then discussed in the light of present theories on pituitary hormones secretion aminergic control and of tricyclic antidepressants effect on these hormones.     

Chronic, but not acute, clomipramine or fluoxetine treatment reduces the spontaneous firing rate in the mesoaccumbens neurons of the rat

In the present study, single-unit extracellular recording was used in male Wistar rats to compare the effects of a single dose (acute treatment) and a 21-day regimen (long-term treatment) with clomipramine (2.5 mg/kg) and fluoxetine (1.0 mg/kg) on the spontaneous firing rate of nucleus accumbens (NAcc) neurons connected with the ventral tegmental area (VTA). A single injection of clomipramine or fluoxetine did not modify the firing rate of NAcc neurons as compared with the control group, whereas a 21-day regimen reduced the firing rate in comparison with a 21-day saline-treated group, specifically for NAcc neurons that were inhibited by VTA electrical stimulation. These results demonstrate that chronic, but not acute, clomipramine or fluoxetine treatment reduces the firing rate of mesoaccumbens neurons, probably by dopaminergic activation, supporting the hypothesis that the NAcc is involved in the actions of at least these antidepressants. However, additional experiments need to be performed in order to delineate the mechanisms by which chronic clomipramine and fluoxetine treatment reduces the firing rate of NAcc neurons in the rat.     

Uptake of serotonin by adult rat corpus callosum is partially reduced by common antidepressants

The corpus callosum (CC) is the main white matter tract involved in interhemispheric brain communication. We establish that uptake of [3H]5-hydroxytryptamine (5-HT) in CC is partially inhibited by some antidepressants. Slices of the adult rat CC had a high-affinity uptake of 5-HT. About 80% of this uptake was Na+ dependent, with a Michaelis-Menten constant, Km, of 420 +/- 80 nM and a rate of 5-HT uptake, Vmax, of 9.5 +/- 0.8 pmol/mg protein/min. The 5-HT uptake was reduced approximately 60% at pH 5 compared with that at pH 7. Fluoxetine (Prozac) inhibited only 43% of 5-HT uptake in a concentration-dependent manner, with an affinity constant, Ki, of 44.7 +/- 10.0 nM. We also studied the effects of other monoamine uptake inhibitors, all at 10 microM, and found that zimelidine, imipramine, and clomipramine inhibited 5-HT uptake in the CC by approximately 30-40%. The fluoxetine-insensitive 5-HT uptake was not altered by high concentrations of dopamine plus norepinephrine. The present data show that Na(+)-dependent 5-HT uptake occurs in the CC and optic nerve and that this uptake is partially sensitive to antidepressants and probably mediated by the serotonin transporter, which may be relevant during depression.     

Protective effects of serotonin reuptake inhibitors, citalopram and clomipramine, against hippocampal CA1 neuronal damage following transient ischemia in the gerbil

To clarify the role of serotonin in cerebral ischemia, we examined the effects of selective serotonin reuptake inhibitors, citalopram and clomipramine, on ischemic neuronal damage in the gerbil. Pretreatment with citalopram (40 mg/kg i.p.) and clomipramine (20 mg/kg i.p.) protected against neuronal destruction of hippocampal CA1 pyramidal cells following 5 min of forebrain ischemia. Furthermore, microdialysis assays showed that a striking increase in extracellular excitatory amino acid levels during ischemia was significantly inhibited by pretreatment with citalopram and clomipramine. However, citalopram (40 mg/kg i.p.) did not alter the extracellular amino acid concentrations in normal gerbils. Thus, serotonin reuptake inhibitors have a protective effect against ischemic neuronal damage. Furthermore, the present result suggests that the protective effect is mediated through prevention of the accumulation of extracellular excitatory amino acids during and after ischemia.