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Tricyclic antidepressive agents(TCAs) are conventional antidepressant. Cytochrome P450(CYP) 2D6 is involved in the hydroxylation of TCAs, while N-demethylation of TCAs is mediated by other such as CYP2C19, 3A4 and 1A2. The elimination of TCAs is impaired by CYP2D6 inhibitors such as quinidine. Newer antidepressants, selective serotonin uptake inhibitors(SSRIs), are also metabolized in the liver. Fluvoxamine, an SSRI, is a potent inhibitors for CYP1A2 and CYP2C19, moderate for CYP3A4 and weak for CYP 2D6. Paroxetine, another SSRI, causes substantial inhibition of CYP2D6 activity. Milnacipran, a serotonin and noradrenaline reuptake inhibitor, is mainly excreted unchanged in urine and some part as its glucronide conjugate. In contrast to many SSRIs, milnacipran is devoid of metabolic inhibition.
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Antidepressant-like activity, as evidenced by marked inhibition of tetrabenazine-induced ptosis, was previously reported for (+/-)-4,5-dihydro-4-phenyl-3H-1,3-benzodiazepine derivatives. Since optimal antitetrabenazine activity was associated with (+/-)-4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine (9k, HRP 543) and the 2-ethyl-3-methyl analogue (10k), the synthesis and evaluation of nuclear-substituted derivatives of these two compounds was also investigated. The initial synthesis involved Friedel-Crafts acylation of substituted benzenes with 2-nitrophenylacetyl chloride to afford 1-aryl-2-(2-nitrophenyl)ethanones 2, which were converted in five steps to (+/-)-alpha-aryl-N-methyl-2-nitrobenzeneethanamines 7. Greater flexibility with respect to the introduction of nuclear substituents was achieved by conversion of 2-nitrotoluene derivatives to 2 via acylation of intermediate beta-(dimethylamino)-2-nitrostyrenes with various aroyl chlorides and hydrolysis. Reductive amination of 2 with methylamine and sodium cyanoborohydride afforded 7 directly and significantly reduced the number of synthetic steps. Reduction of 7a-j to diamines 8a-j and cyclization with appropriate ortho esters gave nuclear-substituted analogues of 9k and 10k. Marked antitetrabenazine activity was associated with many of these compounds. Significant enhancement of activity with respect to the unsubstituted analogues 9k and 10k was not observed, with the exception of 9c which appeared to be slightly more potent than 9k.
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The tricyclic antidepressive agents are still the drugs of choice because of their reliable action and the percentage of successes obtained (60 to 75%), especially in major depressions with deep melancholia. The course of antidepressive drugs is well documented, any depression needs at least three to four months' maintenance treatment after an initial phase of one month's treatment, frequently intravenous treatment is required. Current research is aimed at providing tricyclic agents without anticholinergic activity, the cause of most of their undesirable side-effects.
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Milnacipran is a new antidepressant agent selected from a series of cycloproprane derivatives. The aim of this study was to investigate the acute electrophysiological effects and the tolerance of intravenous administration of this drug in 10 patients without any abnormality as shown in an electrophysiological study done for various complaints. Milnacipran was given over a 30-min period at doses of 0.2 mg/kg (2 patients), 0.4 mg/kg (2 patients) and 0.8 mg/kg (6 patients). The most significant alterations observed in this study were increases in heart rate (average of maximal increase: +19.5% at 50 min, P = 0.06) and systolic blood pressure (average of maximal increase: +21.5% at 10 min, P < 0.005), and decreases in the functional refractory period of the atrium (-3%, P < 0.05), the atrioventricular node (-9%, P < 0.005) and the effective refractory period of the right ventricle (-10.8%, P < 0.05) at 50 min. The sinus node function was improved in nine patients but depressed in one patient with previous slight baseline sinus node alterations. Milnacipran being devoid of both anticholinergic and monoamine oxidase inhibition activities, these alterations could be related to inhibition of noradrenaline uptake leading to an increase of adrenergic activities. No other ECG or electrophysiological parameters were significantly altered. Five of the 10 patients reported transient nausea, four of them for the highest dosage (0.8 mg/kg) and at the moment of peak of milnacipran plasma level. In conclusion, electrophysiological effects of intravenous milnacipran are negligible. These findings differ from those, well described in the literature, for imipramine-like antidepressant agents.(ABSTRACT TRUNCATED AT 250 WORDS)
Overdose of tricyclic antidepressants remains one of the most difficult poisonings to manage optimally in the emergency department, primarily due to the extremely rapid onset of life-threatening symptomatology. The continued high incidence of such overdoses has ensured that morbidity and mortality rates also remain unacceptably high. The development of the "second-generation antidepressants," with apparently different pharmacology and toxicity after overdose, has been an attempt to address this serious medical problem. This report reviews the published literature on the overdose toxicology of the newer cyclic antidepressants currently available in the United States--amoxapine, maprotiline, and trazodone. Nomifensine, released by the FDA in 1984, recently has been voluntarily withdrawn from the world market. Bupropion, released in 1985, also has been voluntarily withdrawn by the manufacturer three months after its release.
INTRODUCTION: Considerable efforts have been made throughout the last 20 years to develop drugs that can replace tricyclic antidepressants as the primary treatment for depression. These efforts are well justified since tricyclic antidepressants, although therapeutically quite efficient, cause several problems, such as side effects and toxicity at therapeutic doses, causing particular problems in the elderly and in patients with congestive heart disease, and giving severe toxicity when taken in overdose. A number of compounds that are pharmacodynamically different from the tricyclics have been developed, and Selective Serotonin Reuptake Inhibitors are such. This group of antidepressives has been developed and widely marked as antidepressant therapy which offers safety and tolerability advantages over tricyclics. Tricyclic antidepressants have been the standard drug treatment for depressive illness, against which the efficacy of new compounds is compared in this investigation. MATERIAL AND METHODS: 30 female inpatients were examined. All patients had to fulfill the inclusion criteria for moderate depressive disorders, according to International Classification of Diseases. The primary efficacy parameters in the study were the changes from baseline Hamilton Rating Scale for Depression with 19 items, total score at endpoint. Patients were evaluated weekly for efficacy and adverse events. Clinicians also rated patients on the Hamilton Rating Scale for Anxiety. In statistical analysis X and T test were used. RESULTS: There was no significant difference between two groups of patients in response to tricyclic antidepressants and selective serotonin reuptake inhibitors. Selective Serotonin Reuptake Inhibitors show less adverse effects compared to tricyclics, so they appeared to be better tolerated. CONCLUSION: The traditional and new antidepressive drugs appeared to be equally effective in the treatment of moderate depressive disorders, but new drugs: Selective Serotonin Reuptake Inhibitors show less adverse effects, compared to the traditional, tricyclic antidepressants.
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