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PubMed1982

(+/-)-4-Aryl-4,5-dihydro-3H-1,3-benzodiazepines. 1. Synthesis and evaluation of (+/-)-4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine and analogues as potential antidepressant agents.

A series of (+/-)-4,5-dihydro-4-phenyl-3H-1,3-benzodiazepines and (+/-)-4,5-dihydro-4-phenyl-1H-1,3-benzodiazepines was synthesized as part of a program to develop novel psychotropics. Of these compounds, (+/-)-4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine (10a, HRP 543) emerged as a potential antidepressant. In in vivo mouse tests (inhibition of tetrabenazine-induced ptosis and potentiation of yohimbine toxicity) which are predictive of antidepressant-like activity, 10a is comparable to amitriptyline. The similarity is also maintained in vitro, as both 10a and amitriptyline inhibit norepinephrine and serotonin uptake into rat brain synaptosomes. No significant inhibition of rat brain monoamine oxidase A or B was found with 10a, nor did the compound potentiate tryptamine-induced seizures. On chronic administration, the number of cortical beta-adrenergic receptor sites was similarly reduced by 10a and desipramine. The anticholinergic activity of clinically useful antidepressants, such as amitriptyline, is a proposed cause of side effects which reduce patient compliance. In contrast to the tricyclics, 10a apparently lacks anticholinergic activity, as evidenced in vitro by negligible displacement of [3H]quinuclidinyl benzylate from rat brain muscarinic receptors and in vivo by insignificant antagonism of the cholinergic stimulation produced by physostigmine or oxotremorine. These data suggest that 10a may be clinically useful as a novel nontricyclic antidepressant which is devoid of anticholinergic side-effect liability. Further evaluation of 10a in nonrodent species is in progress.

Aggression↗
PubMedDate not supplied

[Hematologic toxicity of antidepressive agents].

Drug-induced hematological disorders appear as a rare but serious side effect of the drugs use. According to studies, their frequency is estimated between one and two cases per year for 100,000 subjects, and their mortality is fluctuating between 8 and 17%. Granulocytopenic disorders seem to be responsible for the largest part of that death rate. Antidepressant drugs whose hematotoxicity seems the most frequent are indalpin, mianserin and nomifensin. Nomifensin can induce immunohemolytic anemia, whereas indalpin and mianserin have been at the origin of granulocytopenic disorders. The hematotoxicity of indalpin and mianserin is observed preferentially on elderly female subjects, as observed with most of the compounds responsible for drug-induced hematological disorders.

Agranulocytosis↗
PubMed1985

Behavioural pharmacology of imidazole, a potential antidepressant agent.

Imidazole (IMID) inhibited (+/-) N-n-propylnorapomorphine (NPA) and BHT-920 induced penile erections (PE) and stretching and yawning (SY) in rats as well as apomorphine (APO) induced hypothermia in mice, enhanced shock-elicited aggressiveness in rats and antagonized sleep induced by clonidine in chicks. IMID moreover displayed activity in behavioural tests used in specific screening for antidepressants, potentiating yohimbine toxicity in mice and antagonizing immobility time in the despair test, with a potency in some cases equal to imipramine. IMID per se, depressed motor activity in both mice and rats. The possible mechanism of action and receptors involved are briefly discussed as well as IMID's profile as an antidepressant drug.

Aggression↗
PubMed2000

[Clinical use of new antidepressive agents with dual action (literature review)].

The effective pharmacological treatment of depression started in 1958 with the introduction of iproniazide and imipramine. New agents quickly followed with more specific actions and a safer side effect profile. Very recently, fourth generation antidepressants with dual action have been introduced. These new agents pose a challenging dilemma. Is it better to develop drugs ever more selective towards specific monoamine receptor subpopulations, or drugs that act upon several monoamines in a more focused way? The priority seems to be the investigation of the interactions of the various monoaminergic systems. This paper reviews the clinical use of the new antidepressants that implement the notion of dual action as an important element for efficacy combined with receptor-specific action as a basis for tolerability.

Antidepressive Agents↗
PubMedDate not supplied

[Risk-benefit ratio of drugs. Antidepressive agents as an example].

Medical judgments in therapeutics must be comparative. The toxicity of a drug cannot be considered independently of that of other treatments for the same condition. Such comparison requires new specific methods in order to assess the quantity, quality and validity of available data. A comprehensive analysis is of paramount importance: ideally, all the advantages and disadvantages of different treatments should be simultaneously compared. As far as antidepressants are concerned, the quality of life and the risk of overdose should be borne in mind. Such metaanalyses lead to the identification of a variety of biases likely to distort our judgments related to the risk/benefit ratio of drugs: the bias of perception and of reporting are amongst the most important.

Antidepressive Agents↗
PubMed1994

[New exigencies for new antidepressive agents].

Preclinical trials are mainly concerned with toxicologic and behavioral studies in animals. Clinical trials, in man, require answers to several key-questions: confirmation of the superiority of the compound versus placebo, short, middle, and long-term studies for evaluation of efficacy and safety, international clinical criteria defining the experimental population, research of drug interactions, studies within specific types of population, especially ageing subjects. Heterogeneity of information, for the new antidepressive compounds, is explained by several factors: prescription to out- or in-patients, by general practitioners or specialists. The Marketing Authorization Committee and another committee called "Commission de transparence" assess the risk-benefit ratio, the indications of the drug (acute depressive reaction, prophylaxis of recurrences...), the medical benefit. But these advances in methodological procedures are questionable. Will they allow new discoveries, or, conversely, counteract an inventive clinical practice?

Animals↗
PubMed1992

[The status of fluvoxamine among the antidepressive agents].

Fluvoxamine was administered in an open trial of 50 hospitalized patients with major depression of the melancholic type (DSM-III-R) for an average period of 24.56 days in mean minimal and maximal daily doses of 100-311 mg orally after a wash-out interval of 1-14 days. Treatment achieved complete improvement in 54% and partial improvement in 16% of the patients, significantly more frequently in women than in men. The antidepressant effect of fluvoxamine was confirmed also by a statistically significant reduction of the global HAMD and FKD score, starting on the 7th day of the trial. The therapeutic effect was clinically apparent during the second week of treatment. The best therapeutic effect was achieved in anxiety depressions (65%), to a lesser degree inhibitory depressions (50%) and atypical ones (46%), as apparent from the value of Náhunek's antidepressive index 0.88 which suggests a significant anxiolytic effectiveness of fluvoxamine. Fluvoxamine had a positive effect on the majority of HAMD and FKD items, incl. a depressive mood, anxiety, feelings of guilt, anhedonia, reduced interest and ability, obsession, depressive thoughts and suicidal tendencies. Reduced motor activity, loss of appetite, insight, somatic symptoms, paranoidity and hypochondria were less influenced. At the onset of treatment the preparation did not reduced insomnia and thus in 72% patients hypnotics were added. In the course of fluvoxamine therapy no suicidal attempts were observed although 34 (68%) of the patients initially admitted had suicidal thoughts. Fluvoxamine is well tolerated by patients; as to side-effects gastrointestinal complaints were most frequent (in 28% of the patients).

Adult↗
PubMed1984

The effect of acute zimeldine and alaproclate administration on the acquisition of two-way active avoidance: comparison with other antidepressant agents, test of selectivity and sub-chronic studies.

The dose-dependent effect of acute zimeldine and alaproclate treatment upon the acquisition of two-way and one-way active avoidance in the rat was studied in a single-session and in a repeated-sessions design. Zimeldine (5-20 mg/kg, IP), but not alaproclate, caused disruptions of two-way avoidance acquisition. Acquisition deficits were also caused by citalopram and fluoxetine but not the other antidepressant drugs tested. Zimeldine, but not alaproclate or desipramine, caused a slight but non-significant impairment of one-way active avoidance; neither zimeldine nor alaproclate produced any effects upon fear conditioning and retention testing. The long-term action of p-chloroamphetamine (2 X 10 mg/kg) antagonised the acute zimeldine effect totally, and chronic treatment with zimeldine (15 days, 1 X 50 mumol/kg) and chlorimipramine (15 days, 2 X 10 mumol/kg) also caused some partial blockade of the two-way avoidance deficit. These data seem to suggest some involvement of serotonin (5-HT) in the observed disruptions of two-way active avoidance caused by acute zimeldine treatment.

Alanine↗
PubMedDate not supplied

[Early and intermediate responses as factors predicting efficiency of antidepressive agents].

An important limitation in the treatment of depression is the lack of reliable factors for predicting treatment response. Most of these factors have been related to biological and clinical aspects. A clinical aspect that has proved to reasonably predict long-term efficacy is early response. An adequate early response predicts a good outcome at the long term. The purpose of this study was to quantify the proportion of patients who show no response to a fixed dose of antidepressants after 2,4, and 6 weeks of treatment, and then respond by week 8. Additionally, a subgroup of patients was followed using the same methodology until 12 weeks of treatment. A lack of response by weeks 4 and 6 predicted a final lack of response both at weeks 8 and 12 of treatment. Alternatively, a robust response as early as week 2 predicted a good response by the end of the two treatment periods. These findings should help clinicians revalorate treatment when finding no response after 4 or 6 weeks of treatment.

Adult↗
PubMed1994

[Review of studies in analytical chemistry of antidepressive agents].

The present paper summarizes the methods of determination of psychopharmaceuticals in body fluids, tablets and injections using the techniques not presented in PhBs 4. The methods reported in the present paper increase sensitivity, shorten the time of analysis, decrease the detection limit, and very often eliminate a complicated pretreatment of the sample.

Antidepressive Agents↗
PubMed1993

Antipyrine congeners as antidepressant agents.

1-(N-Antipyrinylglycyl)-3-arylideneamino)-2-thiobarbituric acids (III) were synthesized from 1-arylidene-4-(N-antipyrinyl glycyl)-3-thiosemicarbazones (II). Compounds II in turn were prepared from 4-amino antipyrine. Compounds III were finally converted into 1-(N-antipyrinylglycyl)-3-[(3'-chloro-4-aryl)azitidinyl]-2-t hiobarbituric acids (IV). 4-Aminoantipyrine was also treated with different N-protected amino acids in the presence of N,N'-dicyclohexylcarbodiimide to yield N-(antipyrinylcarbamoyl) substituted alkyl benzamides (V); their debenzoylation yielded 2-(amino-N-antipyrinyl) substituted acetamides (VI). The compounds were screened for their antidepressant activity. Compounds IIId, Va and Vb exhibited activity better than imipramine with less toxicity (ALD50 > 1000 mg/kg).

Amphetamine↗
PubMed1988

[Incidence and therapeutic relevance of the adverse effects of antidepressive agents within the scope of ambulatory neurologic treatment].

Within a postmarketing drug surveillance study the incidence and relevance of ADRs leading to drug discontinuation in therapy of depressed outpatients were examined. In addition, corresponding drug prescribing patterns of patients under routine treatment conditions were recorded. It was found that most psychiatric outpatients were able to identify common ADRs and to differentiate them from the underlying illnesses and comedication. Low-dose therapy was confirmed as routine treatment in the majority of psychiatric outpatients. No differences regarding age, sex, and dosage could be found between patients with further drug intake and those who stopped their antidepressant medication because of ADRs. Such events had been recorded in 11.5% of patients with first prescriptions made by the treating physicians in a monitoring of three months. However, only 0.3% of patients on long-term therapy (that had been initiated at treatment terms preceding the monitoring period) experienced an ADR indicating a decreased risk for drug discontinuation (because of ADR) the longer the patient was on treatment. Knowing ADR(-profiles) of prescribed drugs by treating psychiatrist may aid the treatment of compliance or prevention of ADRs.

Antidepressive Agents↗
PubMedDate not supplied

[Prolactin, depression and antidepressive agents. Review of the literature].

Different neurotransmitters (Dopamine, serotonin, GABA...) and hormones (TRH, oestrogenes...) are involved in the central regulation of prolactin synthesis and release. Under physiological conditions, prolactin levels are related to correlate with age, sex, sexual maturational changes (puberty, menopause...), menstrual cycling... In this review of literature there exists a great amount of data concerned with changes in prolactin in affective disorders illustrating the validity of the biochemical and neuroendocrinological approach specially in depression. Different research paradigms are presently reviewed: measurement of plasma levels of prolactin under basal conditions, in a circadian pattern or after pharmacological challenge with TRH and/or morphine (stimulation), L-dopa and/or dexamethasone (inhibition) and its response to antidepressant drugs. The authors emphasize the contradictory results reported in the literature and suggest the need for extreme caution before considering the validity of prolactin as a biochemical test in depression.

Animals↗
PubMed1999

Acute eosinophilic pneumonia associated with antidepressant agents.

Acute eosinophilic pneumonia is a severe syndrome characterized by fever, lung infiltrates, blood eosinophilia and respiratory failure. We describe a case of acute eosinophilic pneumonia associated with clomipramine and sertraline. A 40-year-old woman was admitted to the emergency department with 37.9 degrees C and respiratory rate of 35 respirations per minute. Blood analysis showed PaO2 = 57.6 mm Hg and HCO3- = 21.7 mmol/l and 12.2% eosinophils. Chest X-ray showed infiltrates in both lower lobes. She was taking clomipramine 25 mg bid for the last 4 weeks and sertraline 50 mg/day for the last week. Other causes of acute eosinophilic pneumonia such as parasitic and fungal infections or collagen diseases were discarded. Both antidepressant were stopped and the patient became afebrile and asymptomatic. A week later the patient was discharged from hospital. Physicians should be aware of this adverse antidepresant reaction which may result in severe pulmonary symptoms.

Acute Disease↗
PubMedDate not supplied

Biosynthesis of catecholamines, uptake of 3H-noradrenaline, and reactivity of cardiovascular system of the rat after chronic and acute treatment with a new antidepressant agent, IPF C-45.

The effect of acute and chronic treatment of rats with IPF C-45 on the following biochemical and pharmacological parameters was tested: catecholamine concentration in brain, heart and adrenals, 3H-noradrenaline uptake by cardiac muscle, the action on catecholamine synthesis following treatment with alpha-methyl-p-tyrosine, reactivity of cardiovascular system to catecholamines and isoproterenol-induced tachycardia. Given chronically, IPF C-45 does not affect noradrenaline uptake by the cardiac muscle. Both chronic and acute administration of the drug decelerates catecholamine biosynthesis by inhibition of tyrosine hydroxylase activity. It seems that the action of IPF C-45, a benzonaphthyridone derivative, affects catecholamine metabolism in a manner distinctly different from that of tricyclic antidepressant drugs.

Adrenal Glands↗
PubMed1982

[Arrhythmias in poisoning with tricyclic antidepressive agents. Successful treatment with physostigmine and sodium].

A 26-year-old female patient was admitted 30 minutes after suicidal poisoning with 750 mg amitriptyline (Saroten), 4800 mg dibenzepine (Noveril retard) and 2100 mg thioridazine (Melleril). Life threatening disturbances of cardiac rhythm occurred in addition to coma, pulmonary insufficiency requiring assisted ventilation, and hypotension. Physostigmine only caused temporary improvement and the arrhythmias only resolved completely after additional administration of NaCl.

Amitriptyline↗
PubMed2000

[New indications for antidepressive agents. Now also in anxiety disorders and premenstrual syndrome?].

Social anxiety and posttraumatic stress disorders are quite common in the adult general population, and often lead to suffering and impaired function in major areas of daily life. In addition to behavioral therapy, pharmacological strategies may bring about significant improvement. Particularly effective are the SSRIs, nefazodone and venlafaxine. Premenstrual syndrome--a common complaint in women of reproductive age--can also be effectively treated with SSRIs.

Adult↗