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Plasma levels, elimination and metabolic fate of 4a-amino-8-chloro-2-methyl-1,2,3,4,4a,10a-hexahydro-10H-benzopyrano[3,2-c]pyridin-10-ylacetic acid lactam, a new antidepressive agent, in rats and dogs.

After single intravenous administration to dogs, 4a-amino-8-chloro-2-methyl-1,2,3,4,4a,10a-hexahydro-10H-benzopyrano[3,2-c]pyridin-10-ylacetic acid lactam (LM 1404) was rapidly distributed. Elimination from plasma was biphasic and dose-independent between 1 and 10 mg/kg, with a half-life for the beta-phase of 4.5 hr. After oral administration, LM 1404 was quickly and nearly completely absorbed. In rats, LM 1404 was rapidly absorbed and eliminated from plasma with a terminal half-life of 2.5 hr. The N-demethylated metabolite (LM 1580), which has a pharmacological activity nearly identical to that of LM 1404, was very abundant in plasma of both species, with half-lives of 13 hr in dogs and 3.5 hr in rats and areas under the curves respectively 2 and 4 times that of LM 1404. Urinary excretion was extensive; unchanged drug amounted to 7 and 1.5% and LM 1580 to 70% in dogs and rats.

Animals↗

[Computer-assisted static and dynamic pupillometry for the characterization of tricyclic antidepressive agent, cianopramine].

Utilizing static and light-evoked dynamic pupillometry, in a placebo-controlled study 14 normal volunteers (9 males and 5 females) in the age range between 22 to 40 years were studied before and after administration of one single dose of 2 mg cianopramine (Ro 11-2465), further after 3 weeks therapy with 1, 2 and 3 mg cianopramine, respectively, and after a superimposed single dose of 3 mg cianopramine on the top of chronic administration. After acute administration of 2 mg cianopramine, marked pupillary changes started already in the 2nd h, peaked in the 4th h and lasted up to the 10th h. While the widening of the pupil indicates the adrenergic and possible noradrenergic effect of cianopramine on the pupil, the attenuation of spontaneous fluctuations suggests concomitant fatigue. The attenuation of the light-evoked narrowing of the pupillary diameter as well as the reduction of pupillary dynamics (increase of latency time and decrease of relative changes) reflect the direct and/or indirect efficacy of cianopramine on the light reaction of the pupil. After chronic administration the changes (as compared with baseline) are still visible although less pronounced than after acute therapy which suggests adaptation phenomena. A superimposed single dose of 3 mg cianopramine in addition to the 3-week chronic treatment did not result in further changes as compared with the chronic effect--with one exception of an additional decrease of spontaneous fluctuations.

Adult↗

Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes.

In vitro studies were conducted to identify the hepatic cytochrome P-450 (CYP) enzymes responsible for the oxidative metabolism of the individual enantiomers of reboxetine. In human liver microsomes, each reboxetine enantiomer was metabolized to one primary metabolite, O-desethylreboxetine, and three minor metabolites, two arising via oxidation of the ethoxy aromatic ring and a third yet unidentified metabolite. Over a concentration range of 2 to 200 microM, the rate O-desethylreboxetine formation for either enantiomer conformed to monophasic Michaelis-Menten kinetics. Evidence for a principal role of CYP3A in the formation of O-desethylreboxetine for (S, S)-reboxetine and (R,R)-reboxetine was based on the results from the following studies: 1) inhibition of CYP3A activity by ketoconazole markedly decreased the formation of O-desethylreboxetine, whereas inhibitors selective for other CYP enzymes did not inhibit reboxetine metabolism, 2) formation of O-desethylreboxetine correlated (r(2) = 0.99; p <.001) with CYP3A-selective testosterone 6-beta-hydroxylase activity across a population of human livers (n = 14). Consistent with inhibition and correlation data, O-desethylreboxetine formation was only detectable in incubations using microsomes prepared from a Baculovirus-insect cell line expressing CYP3A4. Furthermore, the apparent K(M) for the O-desethylation of reboxetine in cDNA CYP3A4 microsomes was similar to the affinity constants determined in human liver microsomes. In addition, (S,S)-reboxetine and (R,R)-reboxetine were found to be competitive inhibitors of CYP2D6 and CYP3A4 (K(i) = 2.5 and 11 microM, respectively). Based on the results of the study, it is concluded that the metabolism of both reboxetine enantiomers in humans is principally mediated via CYP3A.

Antidepressive Agents↗

[Risk factors associated with the consumption of antidepressant agents].

OBJECTIVES: To find the profile of the consumer of anti-depressants, identify risk factors and calculate the prevalence of the under-diagnosis of depression in our milieu. DESIGN: Case-control study. SETTING: Gavà II Health Centre, Barcelona. PARTICIPANTS AND METHODS: The study covered 134 consumers of anti-depressants and 274 controls with no treatment (one group from the Centre, the other from the community) paired for sex, age and general practitioner. The Zung-Conde self-applied depression) scale was administered. MEASUREMENTS AND MAIN RESULTS: 88% of those surveyed were women, with an average age of 50. The prescribing doctor was, in 55% of cases, their general practitioner. The anti-depressants prescribed were mainly (70.9%) from the group of selective inhibitors of serotonin uptake. There were more divorced and widowed people among the cases (p < 0.05). The pathology most often associated with the cases was digestive (31%, p < 0.02). 63% of cases had suffered some event they thought important in the 6 months before prescription. Average score on the Zung test was 51.5% in the cases, and 40% in the controls (p < 0.0001). Using 50 on the Zung scale as the cut-off point, we classified 56% of the cases and 17% of the controls as depressed. CONCLUSIONS: The profile of the consumer of anti-depressants is a women of about 50, living as one of a couple, house-wife, with primary education only, and medium to low social and economic level. The prevalence in the controls of depressive illness neither detected nor treated is similar to that found in other studies. We need to find some instrument to measure attitude, in order to reduce the number of patients who are underdiagnosed in the consulting room.

Antidepressive Agents↗

Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans.

According to in-vitro studies with microsomes from human livers and from yeast expression systems with high CYP2D6 activity, the major oxidation pathway of venlafaxine is catalysed by CYP2D6. In this study, we investigated the role of the CYP2D6 polymorphism and the effects of low-dose quinidine, a selective inhibitor of, CYP2D6, on the disposition of venlafaxine. Fourteen healthy men, eight with the extensive metabolizer and six with the poor metabolizer phenotype were administered venlafaxine hydrochloride 18.75 mg orally every 12 h for 48 h on two occasions (1 week apart); once alone and once during the concomitant administration of quinidine sulfate 100 mg every 12 h. Blood and urine samples were collected under steady-state conditions over one dosing interval (12 h). When venlafaxine was administered alone, the oral clearance of venlafaxine was more than fourfold less in poor metabolizers compared to extensive metabolizers (P < 0.05). This was mainly due to a decreased capability of poor metabolizers to form O-desmethylated metabolites at the position 4 of the aromatic moiety. In extensive metabolizers, quinidine decreased venlafaxine oral clearance from 100 +/- 62 l/h to 17 +/- 5 l/h (mean +/- SD; P < 0.05) without any effects on renal clearance (4 +/- 1 l/h during venlafaxine alone and 4 +/- 1 l/h during venlafaxine plus quinidine). In these individuals, the sequential metabolism of venlafaxine to O-desmethylvenlafaxine and to N,O-didesmethylvenlafaxine was inhibited by quinidine coadministration so that metabolic clearances to O-desmethylated metabolites decreased from 43 +/- 32 l/h to 2 +/- 1 l/h (P < 0.05). In poor metabolizers, coadministration of quinidine did not cause significant changes in oral clearance and partial metabolic clearances of venlafaxine to its various metabolites. Decreased CYP2D6 activity could also be associated with cardiovascular toxicity as observed in four patients during treatment with the drug. Thus, genetically determined or pharmacologically altered CYP2D6 activity represents a major determinant of venlafaxine disposition in humans.

Adult↗

Tricyclic antidepressant agents. II. Effect of oral administration on the uptake of 3-H-noradrenaline and 14-C-5-hydroxytryptamine in slices of the midbrain-hypothalamus region of the rat.

The inhibition of the simultaneous uptake of 3-H-l-noradrenaline (NA) and 14-C-5-hydroxytryptamine (5-HT) in slices of the midbrain-hypothalamus region of the rat brain after oral administration of desipramine, imipramine, nortriptyline, amitriptyline, chlordesipramine and chlorimipramine was determined. All compounds were more active in inhibiting the NA uptake than the 5-HT uptake. This difference was very marked for desipramine, imipramine, nortriptyline and chlordesipramine. Chlorimipramine was almost as active on the 5-HT uptake (ED50 = 35 mg/kg orally) as on the NA uptake (ED50 = 20mg/kg orally) and amitriptyline had low activity on both uptake mechanisms (ED50 greater than 50 mg/kg orally). Desipramine and imipramine were the most active compounds on the NA uptake (ED50 = 8 mg/kg orally for both compounds) and the duration of the action was very long. The ED50 values for nortriptyline and chlordesipramine in inhibiting the NA uptake were about 20 mg/kg orally for both compounds. The inhibition of the 5-HT uptake was less than 50% at 50 mg/kg orally for all compounds except for imipramine (ED50 = 50 mg/kg orally) and for chlorimipramine. The role of the biotransformation for the inhibitory activities of imipramine, chlorimipramine and amitriptyline was investigated in animals pre-treated with SKF 525 A. The inhibitory potency of imipramine was increased by the same factor for both uptake mechanisms probably due to the large increase in the concentration of imipramine in the rat brain, which was demonstrated after the administration of 14-C-imipramine. The inhibitory activity of chlorimipramine was somewhat more increased for the5-HT uptake than for the NA uptake. The low activity of amitriptyline seems to be mainly due to poor resorption, since pretreatment of the animals with SKF 525 A only slightly increased the potency whereas intraperitoneal injection of amitriptyline had a rather marked effect on the NA uptake (ED50 = 11 mg/kg intraperitoneally).

Administration, Oral↗

Determination of diclofensine, an antidepressant agent, and its major metabolites in human plasma by high-performance liquid chromatography with fluorometric detection.

A sensitive and selective high-performance liquid chromatographic assay was developed for the determination of diclofensine (I) and its key metabolites in human plasma. The assay involves deproteinization of plasma, overnight Glusulase incubation to hydrolyze the major metabolite (I-B-glucuronide), extraction of the parent compound and its deconjugated metabolites (I-A, I-B and I-C) from the alkalinized aqueous phase into diethyl ether-ethanol (95:5), the residue of which (containing compounds I, I-A, I-B and I-C) is alkylated with 2-iodopropane dissolved in acetone, using solid potassium hydroxide as a catalyst. The compounds are extracted from the reaction mixture into diethyl ether, after adding ethanol-water-acetic acid (55:40:5), the residue of which is dissolved in 0.05 M sulfuric acid, and reacted with mercuric acetate at 100 degrees C, which oxidizes tertiary tetrahydroisoquinolines to their 3,4-dihydroisoquinoline derivatives, followed by a photochemical reaction in the same solution to form intensely fluorescent isoquinolinium derivatives. An aliquot of this reaction mixture is injected onto a reversed-phase high-performance liquid chromatography column (5-microns Nova-Pac C13 phase in a radial compression cartridge, 10 cm X 8 mm), using the mobile phase 0.25 M triethylammonium phosphate (pH 2.5)-0.25 M acetic acid-methanol-acetonitrile-tetrahydrofuran (150:350:125:375:25). The void volume (Vo) is approximately 1.4 min and the retention times (tR) of the respective isoquinolium derivatives of diclofensine (I) are ca. 3.5 min, internal standard (II) ca. 4.2 min, nordiclofensine (I-A) ca. 5 min, while the phenolic metabolites I-B and I-C give peaks at 6.4 min and 10.4 min, respectively. The derivatives are detected by fluorescence. The method was used to determine plasma concentrations of the parent drug (I) and its major phenolic metabolite I-B (aglycone) in plasma in two normal volunteers following a single oral 45-mg dose and following seven consecutive days of oral dosing of 45 mg three times a day as part of a multiple ascending dose tolerance study.

Alkylation↗

Comparison of serotonin agonistic and antagonistic activities of a new antidepressant agent Trelibet (EGYT-475) and its metabolite EGYT-2760 on isolated rat fundus.

The effects of Trelibet (EGYT-475, N-benzyl-piperazine-picolinyl-fumarate) and its active metabolite (EGYT-2760, N-benzyl-piperazine) on the serotoninergic responses of rat stomach fundus were investigated and compared with those of MCPP (m-chlorophenyl-piperazine) which is the common metabolite of the arylpiperazine antidepressants Trazodone and Etoperidone. The contraction inhibitory potencies of the agents were determined on the equipotent contractions (EC50) to serotonin (5-HT) and prostaglandin F2 alpha (PGF2 alpha). Isotonic contractile responses to 5-HT were not affected by EGYT-475, however, both EGYT-2760 and MCPP produced concentration related and reversible inhibition of the serotoninergic responses. The IC50 values for EGYT-2760 and MCPP were 40.5 +/- 7.5 mumol/l and 125 +/- 35 nmol/l, respectively. The inhibition was selective for the serotoninergic responses, as the equipotent responses to PGF2 alpha were not affected. EGYT-2760 and MCPP displayed not only 5-HT antagonistic, but also partial agonistic activities on the rat fundus preparation. Maximum contractile response of the fundus preparation to MCPP was approximately 25%, to EGYT-2760 was 10% of the maximum response to 5-HT.

Animals↗

[Adverse effects of antidepressive agents in hospitalized geriatric patients].

The frequency, intensity and profile of adverse effects of antidepressants was studied in elderly patients. The series consisted of 102 patients with depression admitted to hospitals in Bratislava and Moscow. The adverse effects of amitriptyline (Amitriptylin Spofa) and maprotiline (Ludiomil Ciba-Geigy) were compared. The assessment done on days 0, 7, and 28 of treatment showed that xerostomia had the highest occurrence rate with both preparations studied. In patients treated with amitriptyline adverse effects were more severe and were recorded more frequently, requiring treatment withdrawal in 3 patients. The overall intensity of adverse effects was significantly higher with amitriptyline (p < 0.05). In the group of patients treated with amitriptyline the adverse effects were more marked in those with severe somatic pathology. The risk of amitriptyline treatment in elderly patients is being emphasized along with the need for monitoring and correcting adverse effects of the treatment. Although maprotiline exhibited a lower occurrence rate of adverse effects, cardiac functions should be regularly checked in patients with preexisting cardiac pathology. (Tab. 2, Fig. 3, Ref. 6.).

Age Factors↗

Physical exercise as a novel antidepressant agent: possible role of serotonin receptor subtypes.

Long-term exercise is associated with an antidepressant effect in patients with mild to moderate forms of nonbipolar depression and appears to be a promising new approach to its treatment. Adaptive changes in serotonin (5-HT) receptor functioning appears to play an important role in mediating the action of various antidepressant treatments. We investigated the adaptive changes in behavioral sensitivity of the 5-HT receptor subtype following 4 weeks of swimming exercise in normal rats, as well as in an animal model of depression (3 week, variety of chronic stressors). 5-HT1A autoreceptor sensitivity was assessed by hyperphagic response induced by 8-OH-DPAT (0.25 mg/kg, IP); 5-HT1A postsynaptic receptor by 5-HT syndrome induced by 8-OH-DPAT (0.75 mg/kg, IP), and 5 Me-ODMT (5 mg/kg, IP); and 5-HT2 receptor by wet dog shakes response induced by quipazine (1 mg/kg, IP) and 5MeODMT (5 mg/kg, IP). It was observed that exercise training in normal rats resulted in enhanced sensitivity of the 5-HT2 receptors along with subsensitivity of 5-HT1A autoreceptors. Exercise, given prophylactically along with chronic stressors, was able to prevent the development of behavioral deficit in the open-field test, and the animals developed remarkably enhanced sensitivity of 5-HT2 receptors. This adaptive supersensitivity of 5-HT2 receptor is also seen after various antidepressant treatments and may play an important role in mediating the antidepressant action of exercise.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

The role of monoamines in the actions of established and "novel" antidepressant agents: a critical review.

Monoaminergic pathways are highly responsive to aversive stimuli and play a crucial role in the control of affect, cognition, endocrine secretion, chronobiotic rhythms, appetite, and motor function, all of which are profoundly disrupted in depressive states. Accordingly, a perturbation of monoaminergic transmission is implicated in the aetiology of depressive disorders, and all clinically available antidepressants increase corticolimbic availability of monoamines. However, their limited efficacy, delayed onset of action, and undesirable side effects underlie ongoing efforts to identify improved therapeutic agents. Sequencing the human genome has raised the hope not only of better symptomatic control of depression, but even of the prevention or cure of depressive states. In the pursuit of these goals, there is currently a tendency to focus on selective ligands of "novel" nonmonoaminergic targets. However, certain classes of novel agent (such as neurokinin(1) receptor antagonists) indirectly modulate the activity of monoaminergic networks. Others may act "downstream" of them, converging onto common cellular substrates controlling gene expression, synaptic plasticity, and neurogenesis. Further, by analogy to the broad-based actions of currently employed drugs, multitarget agents may be better adapted than selective agents to the management of depression-a complex disorder with hereditary, developmental, and environmental origins. It is, thus, important to continue the creative exploration of clinically validated and innovative monoaminergic strategies within a multitarget framework. In this light, drugs combining monoaminergic and nonmonoaminergic mechanisms of action may be of particular interest. The present article provides a critical overview of monoaminergic strategies for the treatment of depressive states, both established and under development, and discusses interactions of novel "nonmonoaminergic" antidepressants with monoaminergic mechanisms.

Antidepressive Agents↗

Effects of viloxazine, an antidepressant agent, on biogenic amine uptake mechanisms and related activities.

The effects of viloxazine, a clinically effective antidepressant, on noradrenaline (NA) and 5-hydroxytryptamine (5-HT) uptake and various related pharmacological activities were determined and compared to those of the tricyclic antidepressants desimipramine, imipramine, and amitriptyline. Viloxazine inhibitied [3H]NA uptake in the mouse and rat heart, being maximally about one half as potent as imipramine with a similar onset, but shorter duration of action than imipramine. The drug did not inhibit [3H]NA uptake in rat medulla or hypothalamus in contrast to desimipramine and imipramine, but it did alter [3H]NA metabolites in a similar manner. Viloxazine, like desimipramine, was a weak blocker of mouse brain 5-HT uptake, but differed from desimipramine as it poteniated 5-HT-mediated functions in the mouse and rat, as did imipramine and amitriptyline, the latter drugs being relatively potent blockers of 5-HT uptake. Viloxazine potentiated the L-DOPA behavioural syndrome in the mouse, antagonized reserpine-induced ptosis and hypothermia in the mouse, and inhibited gastric acid secretion in the rat, but was less potent than the tricyclic antidepressants. No appreciable in vivo inhibition of monoamine oxidase (EC 1.4.3.4.) activity in the mouse was exhibited. Like imipramine, the drug potentiated the ocular effects of L-adrenaline in the rabbit. It was similar to imipramine in potency in potentiating the apomorphine-induced gnawing in the mouse. The drug antagonized oxotremorine-induced hypothermia in the mouse but differed from the tricyclic antidepressants in not exhibiting the anticholinergic effects of blocking the tremors, salivation and lacrimation. Thus, viloxazine exhibits activities related to the biogenic amines both similar to and different from the tricyclics desimipramine, imipramine, and amitriptyline. These actions appear to be of relevance with respect to the antidepressant action of this drug.

Amitriptyline↗

[Possible cross hepatotoxicity between tricyclic and tetracyclic antidepressive agents].

The case is reported of a patient in whom acute hepatitis was induced first by a tricyclic antidepressant (dothiepin) and then by a tetracyclic antidepressant (mianserine). This observation does not confirm previous suggestions that the tricyclic ring is responsible for liver toxicity. However, this theory cannot be rejected as the mechanisms causing toxic hepatitis from tricyclic and tetracyclic antidepressants may well differ. The basis of this hepatoxicity is thus still unexplained. A spateine test was performed and this revealed that the patient was a normal metabolizer.

Acute Disease↗

New bicyclic antidepressant agent. Synthesis and activity of napactadine and related compounds.

A number of N,N'-dialkylarylamidines were synthesized and evaluated for antidepressant activity. Several of these compounds were synthesized from the corresponding nitriles by a new method. Slight structural modification in the series caused a marked change in biological activity and led to compounds as active as imipramine. The arylacetamidine, N,N'-dimethyl-2-naphthaleneethanimidamide hydrochloride (33) (napactadine) was selected for clinical study. Forty-eight additional analogues of 33, including a number of N-alkylamidines, were prepared.

Aggression↗

[Effects of antidepressive agents on glutamatergic autoregulatory presynaptic mechanism in the rat cerebral cortex].

Amitriptyline, imipramine, desipramine, viloxazine, moclobemide and its derivative, novel antidepressant befol (10(-6)-5 x 10(-4) M) decreased by 12-20% K(+)-stimulated 3H-D-asp release from perfused synaptosomes of rat brain cortex. Glutamic acid diethyl ester (GDEE) (10(-4) M) antagonized the effect of amitriptyline, imipramine, desipramine and befol and reversed the effect of moclobemide and viloxazine. Among neuroleptics studied, only carbidine, which possesses antidepressant activity together with antipsychotic one in clinics, decreased 3H-D-asp release by GDEE-sensitive mechanism. Effect of haloperidol and chlorpromazine was not affected by GDEE. It is concluded that autoregulatory mechanism on the terminals of glutamatergic neurons may be involved in the antidepressant action.

Animals↗

[Sexual dysfunction with antidepressive agents. Effect of the change to amineptine in patients with sexual dysfunction secondary to SSRI].

UNLABELLED: Sexual dysfunction secondary to the use of antidepressants, especially clomipramine or SSRI's is an adverse effect that is often underestimated and according to earlier studies, this can affect approximately 60% of the patients. This presents as a decrease in libido, alterations in the ability to reach orgasm/ejaculation, and an erectile dysfunction or a decreased vaginal lubrication. This dysfunction appears to be related with the resulting increase in serotonin and with the stimulation of serotonin 5HT2 receptors. OBJECTIVES: 1) Evaluate the effect of amineptine, a drug with an increased dopamine transmission and scant serotonin transmission, on the sexual function of depressed patients who begin treatment, and 2) evaluate whether the change to amineptine improves the sexual function in patients who presented sexual dysfunction after beginning treatment with a SSRI. MATERIAL AND METHODS: Prospective, observational, open and multicentric design. 111 patients with an average age of 41.3 years (36 men, 75 women) were distributed into three groups: Group 1 (n= 26): patients with depression (DSM IV) who begin de novo treatment with amineptine 200 mg/day. Group 2 (n= 47): depressed patients undergoing treatment with a SSRI who show a favorable response and who present sexual dysfunction secondary to a poorly tolerated treatment, so the treatment is changed to 200 mg/day of amineptine. Group 3 (n= 38): patients with the same characteristics as those of group 2, but whose treatment was changed to 20 mg/day of paroxetine. The < > (Montejo et al, 1996) was used together with the Hamilton Depression Scale, the IGC Scale, and an adverse events scale, over a 6 months follow up period during which visits took place at: baseline, month 1, month 2, month 3, and month 6. RESULTS: In group 1, treated with amineptine from the beginning, of the 5 patients who showed a decrease in the libido at the beginning of the treatment, only one still presented this in the 6th month. The Hamilton Scale decreased from 23.12 (baseline) to 5.25 after 6 months. After substituting amineptine for SSRI's in patients with sexual dysfunction, the incidence of any type of sexual dysfunction decreased significantly from 100% (baseline) to 55.3% after 6 months. (P< 0.001). The incidence of delayed orgasm dropped to 15.8%, anorgasmia to 17.4%, and impotence dropped to 15.8% in this group, with the antidepressant effect that had already been achieved with the SSRI being maintained. However, in group 3 there was barely any improvement on the sexual function after changing to paroxetine (20 mg/day), with the baseline incidence being 100% and the incidence after 6 months being 89.7%. In this last group the antidepressant effect present at the baseline level, was maintained. CONCLUSIONS: Amineptine was shown to be an effective antidepressant in the patients studied, and did not cause secondary sexual dysfunction, and even improved the dysfunction that was present in some patients. In those patients previously treated with SSRI's, amineptine is able to significantly improve the sexual dysfunction and yet maintain the efficacy of the antidepressive treatment used before these 6 months. On the other hand, Paroxetine did not improve the sexual dysfunction of the people in whom this drug substituted another SSRI, as this is an adverse effect common to the entire group of selective serotonin re-uptake inhibiting drugs. Amineptine showed a good safety and tolerance profile. Its most common side effect (anxiety/restlessness) disappeared 2 months after the beginning of the treatment.

Adult↗

Platelet I1-imidazoline binding sites are decreased by two dissimilar antidepressant agents in depressed patients.

Previous studies have indicated that there may be a dysregulation of alpha 2-adrenoceptors and imidazoline receptors in depression. This study compares the effects of chronic antidepressant treatment with a serotonin reuptake inhibitor (fluoxetine) versus a noradrenaline reuptake inhibitor (desipramine) on the binding parameters of the platelet imidazoline binding site (subtype I1) and of the platelet alpha 2-adrenoceptor in depressed patients. After 6 weeks of treatment with either antidepressant, platelet I1 binding sites became normalized (i.e. downregulated). A negative correlation was obtained between plasma epinephrine concentrations and platelet alpha 2-adrenoceptor Bmax values within the samples, but no correlation was obtained between any plasma catecholamine and a platelet I1 binding parameter. An additional finding was the increased affinity of alpha 2-adrenoceptors for p125I-clonidine in untreated depressed patients compared to healthy subjects. Because of the density of platelet I1 binding sites was downregulated by both of the antidepressants, we postulate that a decrease in platelet I1 binding site density may be related to an improved state from depression that these antidepressants produce.

Adrenergic Uptake Inhibitors↗

[Clinical and electroencephalographic study of a new antidepressive agent, mono-methyl-amino-propyl-dibenzo-bicyclo-octadine hydrochloride (Ciba 34, 276 Ba)].

A clinical trial on fifty patients studied a new compound with a quadricyclic structure, Ciba 34.276-Ba or Maprotiline in any category of depression. The product was found to have notable antidepressive properties, capable to act on the melancholic depressions of the manic depressive psychosis and of involutive melancholia. The best results were noted in the neurotic and reactive depressions perhaps because a tranquilizing activity marked in the majority of the cases. The clinical tolerance was found good and the side effects which reminded of those caused by derivates of Imipramine, remained moderate while the biological tolerance was perfect. The modifications of the electroencephalogram were of two types, one of them suggesting thymoanaleptic activity, the other suggesting rather a sedative activity.

Adjustment Disorders↗