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As a part of a research program directed to the discovery of novel antidepressant agents, a series of new hetero[2,1]benzothiazepine derivatives was synthesized. Some of these compounds antagonized the ptosis and motor depression induced by tetrabenazine and were also active in the Porsolt forced swimming test.
Frequently, patients suffering from depressive disorders discontinue antidepressant treatment due to the unpleasant side effects of these medications, particularly in the first month of therapy. Good tolerability (particularly in the early stages of treatment), patient education, and the quality of the relationship between physicians and patients are all common determining factors of patient adherence. Controlled-release antidepressant agents have the potential to improve tolerability early in the course of therapy, one of the most likely periods of dropout from treatment. Side effects for controlled-release formulations are often more favorable because controlled-release formulations exhibit lower peak plasma drug concentrations when compared with immediate-release formulations. Venlafaxine extended-release (XR), bupropion sustained-release (SR), and paroxetine controlled-release (CR) are 3 commonly utilized controlled-release antidepressants that have demonstrated improvement over their immediate-release predecessors in reducing certain adverse effects.
By intramolecular C-H insertion of alpha-diazo-alpha-(phenylsulfonyl)acetamides, gamma-lactams such as the antidepressant agent rolipram were efficiently synthesized in a highly regioselective manner. N-Benzyl moieties were elaborated as amide protecting groups to enhance regioselectivity in C-H activation as well as chemoselectivity over addition reactions. [reaction: see text]
Recent studies have provided evidence that structural remodeling of certain brain regions is a feature of depressive illness, and the postulated underlying mechanisms contribute to the idea that there is more to antidepressant actions that can be explained exclusively by a monoaminergic hypothesis. This review summarizes recent neurobiological studies on the antidepressant, tianeptine (S-1574, [3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt), a compound with structural similarities to the tricyclic antidepressant agents, the efficacy and good tolerance of which have been clearly established. These studies have revealed that the neurobiological properties of tianeptine involve the dynamic interplay between numerous neurotransmitter systems, as well as a critical role of structural and functional plasticity in the brain regions that permit the full expression of emotional learning. Although the story is far from complete, the schema underlying the effect of tianeptine on central plasticity is the most thoroughly studied of any antidepressants. Effects of tianeptine on neuronal excitability, neuroprotection, anxiety, and memory have also been found. Together with clinical data on the efficacy of tianeptine as an antidepressant, these actions offer insights into how compounds like tianeptine may be useful in the treatment of neurobiological features of depressive disorders.
The influence of antidepressants: nomifensine, imipramine, amitriptyline and trazodone on the effect of antiparkinsonian agents: trihexyphenidil and L-DOPA + carbidopa mixture (sinemet) in the model of haloperidol catalepsy was investigated in rats. In some experiments deprenyl, a selective MAO-B inhibitor, was used. It was found that antidepressant drugs in doses not influencing haloperidol catalepsy enhanced significantly the anticataleptic effect of trihexyphenidil and L-DOPA + carbidopa. The most effective in the interaction with both antiparkinsonian agents was nomifensine. Imipramine and trazodone potentiated anticataleptic effect of L-DOPA + carbidopa more strongly than those of trihexyphenidil. The most potent anticataleptic effect was observed after combined treatment of rats with deprenyl and L-DOPA + carbidopa.
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Many cancer patients of the "Service des Maladies Sanguines et Tumorales" of Hôpital Paul-Brousse, Villejuif, are psychologically studied by: the objective and quantified Szondi test, and in the case a depressive syndrome clinical diagnosis is confirmed, this state is quantified by a quintile questionnaire requiring 25 "yes or no" answers (determined by five grades and five stages), in case an inhibition or/and hysteric component is found, the subjects are submitted to the care of a psychoanalyst. A comparative trial of the MAOI, iproniazide, and the tetracyclic analog, mianserine, has been conducted for the search of the most frequently and rapidly active antidepressant agent among them both. The hypothesis that mianserine is less frequently and rapidly active than iproniazide was drawn from our previous experience of 20 years: thus patients presenting a score less than or equal to 12/25 were given mianserine (20 up to 30 mg/day to be possibly increased according to medical decision), while those presenting a score greater than or equal to 13/25 received iproniazide (50 up to 75 mg/day). The patients who failed with mianserine received iproniazide, while those who failed with iproniazide were supposed to receive mianserine. The registered results are the following: a) out of the 25 patients with major depressive syndromes (score greater than or equal to 13) submitted to iproniazide, 16 (61%) were in complete remission (score at 0/25) and five in partial regression (score decreased by more than half); this makes 21 responses in all, i.e. 80%, obtained between the 10th and the 30th days, which is superior to all placebo responses which have varied in the reliable literature from 13 to 70%; b) out of 18 depressive patients submitted to mianserine, only one had benefited of a complete remission and four of a partial regression at the 30th day, which makes 28% responses. Among the side effects of iproniazide, they were two colon meteorism syndromes, easily corrected by prostigmine, five hyposomnia cases corrected by dipotassium chlorazepate, four anejaculation or delay at ejaculation cases which needed eserine when the patients require their disappearance or attenuation. We did not register either hepatic or hyperthermic or hypertensive complications: this is in good agreement with the true incidences, especially that of hypertensive crisis which could be found in serious and scientifically documented articles, to be 0.3 to 0.5% for their appearance, and 1 per 100,000 for their fatal evolution. Among the side effects of mianserine, we have not registered any of the hepatic, renal and cardiac complications mentioned in the literature.(ABSTRACT TRUNCATED AT 400 WORDS)
BACKGROUND: Recent studies have shown that depressive disorder is associated with impaired baroreceptor or baroreflex sensitivity, which is proposed to be a predisposing factor for sudden death in patients with manifest cardiac disease. These studies have not evaluated the afferent and efferent components of the cardiac baroreflex loop or other baroreflex mechanisms that regulate target processes (cardiac metabolism and blood pressure variability) related to the impairment. The objective of this study was to gain more insight into autonomic functioning in depressive disorder to more fully examine the potential basis for increased cardiac mortality. METHODS: The subjects were 28 women and men with unipolar major depression who were taking antidepressant medications and who were in partial remission and free of cardiovascular or other serious disease, and 28 healthy control subjects matched for sex, age, and ethnicity. The two samples were compared for negative affective dispositions (anger expression, hostility, defensiveness, anxiety), spontaneous (closed-loop) baroreflex activity, heart rate, heart rate variability, systolic blood pressure, and heart rate-systolic blood pressure double product under resting conditions. RESULTS: Depressed patients showed a general disposition to anger suppression coupled with higher hostility and anxiety, and lower defensiveness. The patients showed higher general sympathetic activity (high levels of blood pressure, low-frequency heart rate variability) and lower parasympathetic-related activity (high heart rate and reduced high frequency heart rate variability) with affected cardiac metabolism estimated by the double product. Depressed patients had lower baroreflex sensitivity related to a higher gain of the afferent component of the baroreflex without respective gain adjustment of its efferent component (reflex gain 'de-afferentation'). It was coupled with a compensatory higher number of effective baroreflex reactions (reflex gating 're-afferentation'). Antidepressant agents and depressed mood had additional independent effects on baroreflex sensitivity through the efferent component of the cardiac baroreflex loop. CONCLUSIONS: The data indicate that different baroreflex components and mechanisms may be impaired in patients with depression and may contribute to their increased cardiac risk.
Although the efficacy of available antidepressants has been well established in the treatment of mild to moderate depression, clinical research literature on severe depression is more limited, due to lack of a standardized definition for the condition and the resulting inconsistent data. Given the heterogeneous nature of severe depression, reports suggesting noradrenergic as well as serotonergic system involvement in depressive disorders, and the substantive capability of both clomipramine and TCA-SSRI combination to treat severe depression, investigation of dual-action antidepressant agent efficacy in the treatment of severe depression is warranted. The merit of one such combined-action agent, venlafaxine, is reviewed. Efficacy findings from the limited number of comparative clinical trials conducted in the severely depressed patient population suggest that, while venlafaxine has been evaluated in a broad range of depressed patients, this compound may be particularly effective for the severely ill. Pharmacological features of venlafaxine, which may benefit the patient with severe depression, include the possibility of a rapid onset of action and a dose-response curve. Based upon studies comparing venlafaxine with both placebo and other first-line antidepressants, it is concluded that venlafaxine is safe, tolerable, and effective for the treatment of severe depression.
There is some evidence that major depression--in particular, treatment-resistant depression (TRD)--is accompanied by activation of the inflammatory response system and that proinflammatory cytokines may play a role in the etiology of depression. This study was carried out to examine the effects of antidepressive agents, i.e., imipramine, venlafaxine, L-5-hydroxytryptophan, and fluoxetine on the production of interferon-gamma (IFN-gamma), a proinflammatory cytokine, and interleukin-10 (IL-10), a negative immunoregulatory cytokine. Diluted whole blood of fluoxetine-treated patients with TRD (mean age, 50.6+/-3.9 years) and age-matched healthy controls (mean age, 51.6+/-1.7 years) and younger healthy volunteers (mean age, 35.4+/-9.6 years) was stimulated with phytohemagglutinin (1 microg/mL) and lipopolysaccharide (5 microg/mL) for 48 hours with and without incubation with the antidepressants at 10-6 M and 10(-5) M. IFN-gamma and IL-10 were quantified by means of enzyme-linked immunoassays. The ratio of IFN-gamma to IL-10 production by immunocytes was computed because this ratio is of critical importance in determining the capacity of immunocytes to activate or inhibit monocytic and T-lymphocytic functions. All four antidepressive drugs significantly increased the production of IL-10. Fluoxetine significantly decreased the production of IFN-gamma. All four antidepressants significantly reduced the IFN-gamma/IL-10 ratio. There were no significant differences in the antidepressant-induced changes in IFN-gamma or IL-10 between younger and older healthy volunteers and TRD patients. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-noradrenaline reuptake inhibitors, as well as the immediate precursor of serotonin, have a common, negative immunoregulatory effect by suppressing the IFN-gamma/IL-10 production ratio. It is suggested that the therapeutic efficacy of antidepressants may be related to their negative immunoregulatory effects.
OBJECTIVES: This article examines the use of antidepressant medication in the treatment of major depression in the Department of Veterans Affairs (VA) during the 2001 fiscal year and considers the relationship of patient, drug, provider, and facility to adherence to medication treatment guidelines. METHODS: Prescription drug records for all VA outpatients diagnosed with major depression (International Classification of Diseases, 9th edition, code 296.2 or 296.3) were collected for October 2000 through September 2001. Indicators were constructed that noted whether patients newly treated with antidepressants (i.e., with no prescription in the previous 8 weeks) received at least 180 days (continuation phase) of antidepressant drug treatment (84- and 140-day measures were also considered). Logistic regression with and without center fixed effects and generalized estimation equations were used to identify patient, drug, and facility characteristics that were associated with these treatment quality indicators. RESULTS: Of the 27,713 patients in the final sample, 54% received at least 181 days of treatment. This is higher than recent rates reported by Health Employer Data and Information Set (HEDIS) for the general population, although our measures and those used by HEDIS are not exactly the same. Women, married patients, older patients, and whites were more likely than others to have higher-quality antidepressant drug treatment. Contrary to previous research, we find few significant differences among specific antidepressant agents prescribed in this large sample. Comorbid substance abuse was associated with fewer days of treatment, whereas other psychiatric comorbidities increased the length of treatment. We found few differences resulting from provider type. Although significant differences among facilities were found in the unadjusted rates (similar to those used by HEDIS), these diminished greatly after controlling for relevant covariates. CONCLUSIONS: In the nation's largest mental health system, quality of pharmacotherapy for depression, at least by one standard measure, is relatively good. We found the specific antidepressant drug used has little impact on quality. In considering differences among facilities, we found that it is critical to control for relevant patient characteristics.
Some forms of anxiety and affective disorder, such as panic disorder and major depression, appear distinct, but frequently symptoms of depression and anxiety occur together. The comorbidity of anxiety and depression not only has implications for the differential diagnosis of the disorder but affects the severity and course of illness and its responsiveness to treatment. The results of studies of atypical depression suggest that this form of depressive illness responds better to monoamine oxidase inhibiting medications than to tricyclic antidepressant agents, and this preferential responsiveness may in fact define the boundaries of atypical depression. The serotonin selective reuptake inhibitor paroxetine seems to have a beneficial effect on symptoms of anxiety and agitation in depressed patients. Further clinical research is needed, however, to determine the best way to manage depression with anxiety and atypical depression.
A body of evidence indicates that the therapeutic activity of antidepressants is connected with their modulatory effect on the inflammatory response system and cell-mediated immunity. The present study was carried out to examine the effects of antidepressant agents, such as imipramne, venlafaxine, l-5-hydroxytryptophan, fluoxetine and a combination of l-5-hydroxytryptophan and fluoxetine, on the production of the pleotrophic cytokines TNF-alpha and IL-6. Diluted whole blood from fluoxetine-treated patients with treatment-resistant depression (TRD) (mean age: 50.6+/-3.9 years), age-matched healthy controls (mean age: 51.6+/-1.7 years) and younger healthy volunteers (mean age: 35.4+/-1.7 years) was stimulated with phytohemagglutinin (PHA) and lipopolysaccharide (LPS) for 48 h with or without incubation with the antidepressants at 10(-6) and 10(-5) M. The major findings of this study are: (1). imipramine and venlafaxine (at the higher concentration), 5-HTP (at lower and higher concentrations) and a combination of 5-HTP and fluoxetine (both at the lower concentration) increased the production of IL-6; (2). all drugs used did not affect TNF-alpha production. IL-6 production was significantly higher in depressed patients than in age-matched volunteers, whereas TNF-alpha production was significantly higher in older volunteers than in younger ones. We speculate that the therapeutic activity of these antidepressants is at least partly connected with their effect on the cytokine network and IL-6 production.
There are controversial results of clinical trials on the antidepressant effects of Hypericum perforatum, while several preclinical studies describe antidepressant properties for Hypericum extracts. This study evaluates the antidepressant effect of two commercially available hydroalcoholic extracts of H. perforatum standardized to contain 0.3% hypericin in comparison to imipramine (IMI), in the forced swimming test (FST). Wistar rats were treated with different doses of two Hypericum extracts, of hypericin or of IMI and submitted to the FST. The experiments were videotape recorded to detail immobile and active behaviors of rats during the procedures. The imported extract tested and hypericin did not modify rats' behaviors in the test, while IMI, a classical antidepressant, significantly shortened immobility and prolonged climbing behavior during forced swimming. The locally produced Hypericum extract significantly increased immobility duration as compared to the controls at the same time as climbing efforts were decreased. Therefore, the two different commercially available Brazilian hydroalcoholic H. perforatum extracts did not show the expected effects in a screening test for antidepressant agents, on the contrary, one of the extracts promoted a depressant-like effect in rats. Therefore, these extracts available to the population differ from other Hypericum extracts. At which step of the production or commercialization chain these extracts probably lost their therapeutic potential remains to be evaluated.
The potential use of rapid eye movement (REM) sleep effects as a biomarker for the therapeutic effects of antidepressants in healthy volunteers is reviewed. A literature search was performed to select studies investigating the effects of antidepressants on REM sleep. To assess the specificity of REM sleep effects as a biomarker, the effects of other central nervous system drugs on REM sleep were also investigated. A significant REM sleep reduction was shown for 16 of 21 investigated antidepressants after single-dose (mean reduction 34.1%) and for 11/13 drugs after multiple-dose administration (mean reduction 29.2%). The median increase in REM latency was approximatety 60% after single- or multiple-dose administration. REM sleep effects were linearly normalized to therapeutic doses, by dividing the REM sleep effect by the investigated dose and multiplying by the therapeutic dose. Normalized REM sleep effects were highly variable (range -27.0% to 81.8% for REM sleep; range -17.0% to 266.3% for REM latency) and demonstrated no relationship with relevant pharmacological properties of the investigated drugs. No quantifiable dose-response relationship could be constructed after single and multiple dose administration. REM sleep effects were not specific for antidepressants. Benzodiazepines, for example, caused an average dose normalized REM sleep reduction of 8.7% and a median 8.6% increase of REM latency. This review demonstrates that although REM sleep effects occur with most of the antidepressants, it is by itself of limited value as a biomarker for antidepressant action. The specificity for antidepressants is limited, and it does not show a quantitative dose-response relationship to antidepressant agents. This is at least partly due to the complex relationships between drug pharmacokinetics and the variable time course of REM and other sleep stages throughout the night. Models that take these complex relationships into account may provide more comprehensive and quantifiable results.
Major antidepressant agents increase synaptic levels of monoamines. Although the monoamine hypothesis of depression remains a cornerstone of our understanding of the pathophysiology of depression, emerging data has suggested that the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subtype of glutamate receptor may also play a pivotal role in depression. Positive allosteric modulators of AMPA receptors increase brain levels of brain-derived neurotrophic factor (BDNF) that impacts the viability and generation of neurons in key brain structures. AMPA receptor potentiators are active in rodent models predictive of antidepressant efficacy. The mechanisms by which AMPA receptor potentiators produce these biological effects, however, are uncertain. Current evidence points to an antidepressant mechanism that is independent of monoaminergic facilitation that is driven by neurogenesis, a process facilitated by increased BDNF expression. However, alternative hypotheses need to be considered given uncertainties in the relationship between BDNF increases and the effects of conventional antidepressant medications. Electrophysiological and protein conformational data indicate that structural variants of AMPA receptor potentiators can differentially modulate AMPA receptor-mediated currents, although the manner in which this impacts antidepressant efficacy is yet to be understood. Conventional antidepressants such as fluoxetine positively modulate AMPA receptors. This potentiation is engendered by specific phosphorylation pathways activated through the dopamine- and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32). Other novel compounds with antidepressant-like effects in rodents may also produce their in vivo effects through potentiation of AMPA receptors. Thus, AMPA receptor potentiation might be a general mechanism through which the clinical outcome of antidepressant efficacy is achieved.