Interaction of antidepressants with clonidine on rat brain total 3-methoxy-4-hydroxyphenylglycol.

The effects of some antidepressants on brain total 3-methoxy-4-hydroxyphenylglycol (MHPG) were studied in the rat. Desipramine decreased and mianserine increased the brain total MHPG concentration while the other antidepressants had no effect. They were also the only antidepressants that attenuated the lowering action of clonidine on brain total MHPG, but possibly through different mechanisms. Two tertiary amine tricyclic antidepressants, amitriptyline and imipramine, appeared to enhance the lowering action of clonidine on brain total MHPG. The results suggest that antidepressants are heterogeneous in their action on brain noradrenergic mechanisms in the rat.     

Use of antidepressants among people committing suicide in Sweden.

OBJECTIVE--To analyse the outcome of depression in the Swedish population as reflected by the detection of antidepressants in a national forensic toxicological screening programme of unnatural deaths. DESIGN--Antidepressants detected by the National Laboratory of Forensic Chemistry were related to data on use expressed in person years of exposure. SUBJECTS--All 7000 cases of unnatural death with results from forensic toxicological screening in 1990-1; this included 3400 (85%) of the 4000 cases of suicide in Sweden. MAIN OUTCOME MEASURES--Number of findings of antidepressants in the screening programme and number of findings of different antidepressants in relation to their use. RESULTS--Antidepressants were found in 585 screening tests, corresponding to 542 subjects or less than 16% of the 3400 cases of suicide. Newer, less toxic antidepressants were found more often than the older compounds. Toxic concentrations of antidepressants were found in only 190 cases (5.6%). CONCLUSION--A consistent finding in surveys of suicide is that about half of the patients who commit suicide are depressed. The current data suggest that most depressed patients who commit suicide are not taking antidepressants immediately before death. Therapeutic failure may be a greater problem with antidepressants than toxicity as the results did not indicate any advantage of the newer, less toxic antidepressants. All causes of death should be included in risk analyses, thereby providing an estimate of effectiveness as well as toxicity of antidepressants.     

Dual ultraviolet wavelength high-performance liquid chromatographic method for the forensic or clinical analysis of seventeen antidepressants and some selected metabolites

A sensitive method suitable for the determination of tricyclic and other antidepressants in postmortem and clinical specimens is presented. The procedure, which utilizes reversed-phase HPLC combined with dual ultraviolet wavelength detection, enables the separation of 17 commonly prescribed antidepressants and some selected metabolites in a single extraction. Peak purity was confirmed using absorbance ratios at 220 nm and 254 nm wavelengths and revealed little interference from other eluting analytes. The blood detection limit for most antidepressants was 50 ng/ml. The most commonly observed antidepressants in 281 forensic cases analysed over a two-year period with the described method were dothiepin, amitriptyline, nortriptyline and doxepin.     

Effects of antidepressive agents on tolerance of hypoxia and physical exercise]

In experiments on mice and rats we studied the influence of antidepressants on hypoxic and physical tolerance. The antidepressants pyrazidol, azaphen, imipramine and moclobemide as well as the nootropic drug piracetam prolonged the life of animals in conditions of hypoxic and hemic hypoxia and increased the survival rate of rats in circulatory hypoxia. In experiments on mice antidepressants increased also the time of swimming.     

Enhancement of antidepressant potency by a potentiator of AMPA receptors

1. AMPA receptor potentiators (ARPs) exhibit antidepressant-like activity in preclinical tests (for example, the forced swim test) that are highly predictive of efficacy in humans. Unlike most currently used antidepressants, ARPs do not elevate extracellular levels of biogenic amines (e.g., 5HT, NE) in prefrontal cortex at doses that are active in the forced swim test.2. The present series of experiments examined the effects of combining the ARP, LY 392098, with biogenic amine-based antidepressants in the forced swim test. Male, NIH Swiss mice were placed in a cylinder of water and observed for attempted escape behaviors and immobility.3. LY 392098 dose-dependently decreased immobility as did a range of classical antidepressants. At doses of LY 392098 below those that decreased immobility, this compound significantly increased the potency with which fluoxetine and citalopram (SSRI antidepressants), imipramine (tricyclic antidepressant), duoxetine (norepinephrine/serotonin uptake blocker), nisoxetine (norepinephrine uptake inhibitor), and rolipram (PDE4 inhibitor) decreased immobility in the forced swim test with potency shifts upward of 5-fold (fluoxetine, imipramine, and rolipram). Likewise, ineffective doses of the traditional antidepressants potentiated the effects LY 392098 with shifts in the dose-effect functions that were 10-fold or more for citalopram, fluoxetine, imipramine, and duloxetine.4. Combined with other evidence for a role of AMPA receptors in the efficacy of antidepressants, the current data suggest that the addition of an ARP may augment the activity and perhaps the onset of the therapeutic effects of biogenic amine and second messenger-based antidepressants.     

The antiulcer action of antidepressants. II. The effect of the antidepressants inkazan, azafen, and OF-743 in combination with arginine on ethanol-evoked damage to the gastric mucosa in rats]

Mucosal gastric damages in rats induced by intragastric ethanol introduction decreased considerably on the background of action of one of the antidepressants (asaphen, inkasan and OF-743) in combination with arginine. The combination OF-743 with arginine has the largest protective action, the least one--asaphen with arginine. A comparison of protective action of some antidepressants with action of antidepressants in combination with arginine revealed a tendency to more expressed antiulcerogenic effect in studied combinations.     

抑郁症发病机制及中药治疗研究进展

抑郁症是一种常见的精神疾病,发病率高,严重威胁着人类的健康,但其病因、发病机制尚不清楚,由于合成抗抑郁药大多存在抗抑郁谱窄、不良反应大、药价高和易复发等缺陷,近年来随着人们对抑郁症发病机制的研究,人们逐渐把目光投向传统的中医药,以期从中寻找出多靶点、低毒的抗抑郁药。现对近年来抑郁症的病因、病机、及中药治疗的研究情况做一综述     

The antidepressants imipramine, clomipramine, and citalopram induce apoptosis in human acute myeloid leukemia HL-60 cells via caspase-3 activation.

Some widely used antidepressants such as imipramine, clomipramine, and citalopram have been found to possess antineoplastic effects. In the present study, these compounds were found to induce apoptotic cell death in human acute myeloid leukemia HL-60 cells. Apoptosis induced by the antidepressants was identified by electron microscopy and conventional agarose gel electrophoresis and was quantitated by propodium iodide staining and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) via flow cytometry. Treatment with apoptosis-inducing concentrations of the antidepressants (80 microM imipramine, 35 microM clomipramine, or 220 microM citalopram) caused induction of caspase-3/caspase-3-like activity, which was monitored by the cleavage of poly(ADP-ribose) polymerase (PARP), the loss of the 32 kD caspase-3 (CPP32) precursor, and the cleavage of the fluorescent CPP32-like substrate PhiPhiLux. Pretreatment with a potent caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone (zVAD-fmk) inhibited antidepressant-induced CPP32/CPP32-like activity and apoptosis. Furthermore, activation of caspase induced by the antidepressants was preceded by the hypergeneration of intracellular reactive oxygen species (ROS). These results suggested that the antidepressants may induce apoptosis via a caspase-3-dependent pathway, and induction of apoptosis by the antidepressants may provide a clue for the mechanism of their antineoplastic effects.     

Antidepressants are a rational complementary therapy for the treatment of Alzheimer's disease

There is a high prevalence rate (30-50%) of Alzheimer's disease (AD) and depression comorbidity. Depression can be a risk factor for the development of AD or it can be developed secondary to the neurodegenerative process. There are numerous documented diagnosis and treatment challenges for the patients who suffer comorbidity between these two diseases. Meta analysis studies have provided evidence for the safety and efficacy of antidepressants in treatment of depression in AD patients. Preclinical and clinical studies show the positive role of chronic administration of selective serotonin reuptake inhibitor (SSRI) antidepressants in hindering the progression of the AD and improving patient performance. A number of clinical studies suggest a beneficial role of combinatorial therapies that pair antidepressants with FDA approved AD drugs. Preclinical studies also demonstrate a favorable effect of natural antidepressants for AD patients. Based on the preclinical studies there are a number of plausible antidepressants effects that may modulate the progression of AD. These effects include an increase in neurogenesis, improvement in learning and memory, elevation in the levels of neurotrophic factors and pCREB and a reduction of amyloid peptide burden. Based on this preclinical and clinical evidence, antidepressants represent a rational complimentary strategy for the treatment of AD patients with depression comorbidity.     

Antidepressant drugs in the elderly: Are the indications as long term as the treatment?

In a community study of 761 people aged 70 years and over 45 (5·9%) were found to be taking long term tricyclic antidepressants. Forty four were compared with matched controls. There was no evidence that tricyclic antidepressants were being used to compensate for poor physical health or function. Twenty subjects had a clear history of depression; three of these required additional treatment and five might have coped without continued drug treatment. Twelve of the remainder had started treatment with tricyclic antidepressants as hypnotics and 11 as a trial because of suspected depression. They had continued taking the drugs over a long period.Regular review of both the adequacy of and the necessity for continued treatment with tricyclic antidepressants in the elderly is recommended.     

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

Oxidative stress has long been associated with aging and has recently been linked to psychiatric disorders, including psychosis and depression. We identified multiple antipsychotics and antidepressants that extend Caenorhabditis elegans lifespan and protect the animal from oxidative stress. Here, we report that atypical antidepressants activate a neuronal mechanism that regulates the response to oxidative stress throughout the animal. While the activation of the oxidative stress response by atypical antidepressants depends on synaptic transmission, the activation by reactive oxygen species does not. Lifespan extension by atypical antidepressants depends on the neuronal oxidative stress response activation mechanism. Neuronal regulation of the oxidative stress response is likely to have evolved as a survival mechanism to protect the organism from oxidative stress, upon detection of adverse or dangerous conditions by the nervous system.     

Inhibition of food intake in the rat

The effects of single oral administrations of tricyclic antidepressants (imipramine and desipramine), an atypical antidepressant (nomifensine), known anorexic agents, haloperidol, and diazepam on food intake were compared in Sprague-Dawley rats over a 4-day test period. The tricyclic antidepressants produced decreases in food intake during the total 4-day test period following their administration. In contrast, the anorexic agents (d-amphetamine, cocaine, mazindol, fenfluramine and quipazine), nomifensine, and haloperidol produced decreases in food intake only on the day of their administration. Diazepam produced an increase in food intake only on the day of its administration. In addition to revealing that high doses of antidepressants can decrease food intake, this model appears to show some specificity for tricyclic antidepressants.     

Amitriptyline and imipramine inhibit the release of acetylcholine from parasympathetic nerve terminals in the rat iris

The electrically stimulated release of [3H]acetylcholine from the parasympathetic nerve terminals of the rat iris in vitro is increased in a dose-dependent manner by scopolamine but is decreased by the tricyclic antidepressants amitriptyline and imipramine. The increased release in the presence of scopolamine seems to be due to the blockade of a presynaptic muscarinic autoreceptor that, in the drug-free state, inhibits the release of acetylcholine. However, at drug concentrations that should have comparable antimuscarinic potency, the antidepressants inhibit the release of acetylcholine. This suggests that the anticholinergic side effects of the antidepressants may be due to the reduced release of acetylcholine from parasympathetic nerve terminals as well as a possible direct postsynaptic muscarinic receptor blocking action. Whatever the mechanism of this action, the antidepressants do not have the same effect as scopolamine at the presynaptic muscarinic autoreceptor in the rat iris.     

Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression.

OBJECTIVE--A comprehensive meta-analysis of clinical trial data was performed to assess the possible association of fluoxetine and suicidality (suicidal acts and ideation). DESIGN--Retrospective analysis of pooled data from 17 double blind clinical trials in patients with major depressive disorder comparing fluoxetine (n = 1765) with a tricyclic antidepressant (n = 731) or placebo (n = 569), or both. MAIN OUTCOME MEASURES--Multiple data sources were searched to identify patients with suicidal acts. Suicidal ideation was assessed with item 3 of the Hamilton depression rating scale, which systematically rates suicidality. Emergence of substantial suicidal ideation was defined as a change in the rating of this item from 0 or 1 at baseline to 3 or 4 during double blind treatment; worsening was defined as any increase from baseline; improvement was defined as a decrease from baseline at the last visit during the treatment. RESULTS--Suicidal acts did not differ significantly in comparisons of fluoxetine with placebo (0.2% v 0.2%, p = 0.494, Mantel-Haenszel adjusted incidence difference) and with tricyclic antidepressants (0.7% v 0.4%, p = 0.419). The pooled incidence of suicidal acts was 0.3% for fluoxetine, 0.2% for placebo, and 0.4% for tricyclic antidepressants, and fluoxetine did not differ significantly from either placebo (p = 0.533, Pearson''s chi 2) or tricyclic antidepressants (p = 0.789). Suicidal ideation emerged marginally significantly less often with fluoxetine than with placebo (0.9% v 2.6%, p = 0.094) and numerically less often than with tricyclic antidepressants (1.7% v 3.6%, p = 0.102). The pooled incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for placebo, and 3.6% for tricyclic antidepressants. The incidence was significantly lower with fluoxetine than with placebo (p = 0.042) and tricyclic antidepressants (p = 0.001). Any degree of worsening of suicidal ideation was similar with fluoxetine and placebo (15.4% v 17.9%, p = 0.196) and with fluoxetine and tricyclic antidepressants (15.6% v 16.3%, p = 0.793). The pooled incidence of worsening of suicidal ideation was 15.3% for fluoxetine, 17.9% for placebo, and 16.3% for tricyclic antidepressants. The incidence did not differ significantly with fluoxetine and placebo (p = 0.141) or tricyclic antidepressants (p = 0.542). Suicidal ideation improved significantly more with fluoxetine than with placebo (72.0% v 54.8%, p less than 0.001) and was similar to the improvement with tricyclic antidepressants (72.5% v 69.8%, p = 0.294). The pooled incidence of improvement of suicidal ideation was 72.2% for fluoxetine, 54.8% for placebo, and 69.8% for tricyclic antidepressants. The incidence with fluoxetine was significantly greater than with placebo (p less than 0.001) and did not differ from that with tricyclic antidepressants (p = 0.296). CONCLUSIONS--Data from these trials do not show that fluoxetine is associated with an increased risk of suicidal acts or emergence of substantial suicidal thoughts among depressed patients.     

Prolonged administration of antidepressants induces changes in the pulsed release but not in the reverse uptake of biogenic amines

The experiments on rats have shown that antidepressant concentrations that cause 50% inhibition of 14C-NA and 3H-HT uptake by brain slices remain unchanged following prolonged administration of antidepressants (imipramine, pirazidole, harmane and its derivatives--C-153, C-307, C-394, C-395), as compared to the control. Electrical stimulation of brain slices upon long-term treatment of rats with antidepressants and preincubation with 14C-NA and 3H-HT enhanced presynaptic release of radioactive mark at concentrations of antidepressants (EC2) 3-14 times lower than those in the control animals. Long-term antidepressant administration reduces the inhibitory influence of clonidine and HT on presynaptic release of 14C-NA and 3H-HT by brain slices. It is suggested that long-term administration of antidepressants decreases the sensitivity of terminal axons of NA- and HT-ergic neurons to autoinhibitory effect of neurotransmitter release.     

Inhibition of acetylcholinesterase from Electrophorus electricus (L.) by tricyclic antidepressants

The effects of tricyclic antidepressants drugs (TCA) amitriptyline, imipramine and nortriptyline, on purified Electrophorus electricus (L.) acetylcholinesterase (AChE; acetylcholine hydrolase, EC 3.1.1.7) were studied using kinetic methods and specific fluorescent probe propidium. The antidepressants inhibited AChE activity by a non-competitive mechanism. Inhibition constants range from 200 to 400 microM. Dimethylated amitriptyline and imipramine were more potent inhibitors than the monomethylated nortriptyline. Fluorescence measurements using bis-quaternary ligand propidium were used to monitor ligand-binding properties of these cationic antidepressants to the AChE peripheral anionic site (PAS). This ligand exhibited an eight-fold fluorescence enhancement upon binding to the peripheral anionic site of AChE from E. electricus (L.) with K(D)=7 x 10(-7)M. It was observed that TCA drugs displaced propidium from the enzyme. On the basis of the displacement experiments antidepressant dissociation constants were determined. Similar values for the inhibition constants suggest that these drugs have similar affinity to the peripheral anionic site. The results also indicate that the catalytic active center of AChE does not participate in the interaction of enzyme with tricyclic antidepressants. These studies suggest that the binding site for tricyclic antidepressants is located at the peripheral anionic site of E. electricus (L.) acetylcholinesterase.     

Experimental methods for evaluation of psychotropic agents in rodents: II-Antidepressants

Rodent models of clinical depression are extensively used for the evaluation of putative antidepressants. In the present review, the available experimental methods which can be utilized by most laboratories involved in preclinical screening of antidepressants, have been discussed. The methods have been categorized on the basis of induction of the depressive state or on the assumption that monoamine deficiency leads to depression. These methods have been critically validated in terms of efficacy of standard antidepressants in these tests and, in some cases, by the neurochemical basis of depression, namely, the deficient monoaminergic theory of clinical depression.     

General practitioners' perceptions of the tolerability of antidepressant drugs: a comparison of selective serotonin reuptake inhibitors and tricyclic antidepressants.

OBJECTIVE: To examine inceptions and discontinuations of antidepressants in general practice. DESIGN: An observational study analysing data from an ongoing cross sectional postal survey. Every three months a representative sample of 250 doctors recorded prescribing activity for four weeks. This provided 4000 general practitioner weeks of recording per year. SETTING: A representative panel of general practitioners in England, Wales, and Scotland. SUBJECTS: Patients who began a new course of an antidepressant or had their treatment stopped or changed by the general practitioner between 1 July 1990 and 30 June 1995. MAIN OUTCOME MEASURES: Numbers of patients prescribed a new course of antidepressant; numbers discontinuing treatment; the ratio of antidepressant discontinuations to antidepressant inceptions; reasons for discontinuation; proportion of switches to another antidepressant. RESULTS: There were 13,619 inceptions and 3934 discontinuations of selective serotonin reuptake inhibitors and tricyclic antidepressants during the study. The number of newly prescribed courses of antidepressants increased by 116%, mostly due to an increase in prescribing of serotonin reuptake inhibitors. The ratio of total discontinuations to inceptions was significantly lower for serotonin reuptake inhibitors (22%) than for tricyclic antidepressants (33%). Differences persisted when controlled for age and sex of patients and severity of depression. However, there was more switching away from selective serotonin reuptake inhibitors when they failed (72%) than from tricyclic antidepressants (58%). CONCLUSIONS: Selective serotonin reuptake inhibitors are less likely than tricyclic antidepressants to be discontinued. A prospective study is needed in general practice to assess the implications of differences in discontinuation rates and switches on clinical and economic outcomes.     

Soluble Urokinase Plasminogen Activator Receptor as a Marker for Use of Antidepressants

Objectives

Inflammation is involved in the pathogenesis of depression. A few cross-sectional population-based studies have found that depression is associated with increased levels of inflammatory markers. Soluble urokinase plasminogen activation receptor (suPAR) is known to be a stable marker for inflammation. We investigated the bidirectional association between suPAR levels and use of antidepressants.

Methods

suPAR level was measured in 9305 blood donors and analysed in relation to 5-years follow-up data on purchase of antidepressants and hospital diagnoses of depression from a nationwide Danish register.

Results

For men and women without prior use of antidepressants we found a significantly higher risk for incident use of antidepressants with higher suPAR values. For men, the risk of first use of antidepressants increased by 72% from the 1^st to the 4^th quartile (HR = 1.72, 95% CI: 1.11–2.69). For women, it increased by 108% from the 1^st to the 4^th quartile (HR = 2.08, 95% CI: 1.45–2.98). Previous use of antidepressants was also significantly associated with higher suPAR levels (p = 0.002).

Conclusions

High suPAR levels are associated with an increased risk for both previous and future use of antidepressants in healthy men and women. High suPAR are also associated with increased risk for a hospital diagnosis of depression.