Effects of antidepressant drugs on histamine-H1 receptors in the brain

The histamine-H1 receptor blocking properties of a number of structurally different antidepressant drugs have been evaluated using a 3H-mepyramine binding assay and a guinea-pig ileum preparation. The tricyclic antidepressants all inhibited the histamine-H1 receptor. Some newer antidepressant drugs, such as zimelidine and nomifensine were devoid of activity while others, such as iprindole and mianserin were very potent. It is concluded that antagonistic effects on the histamine-H1 receptor is not associated with the therapeutic efficacy in depression, but may contribute to the sedative effects of the antidepressant drugs.     

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.     

Older versus newer antidepressants: substance P or calcium antagonism?

Substance P (SP) is possibly involved in the pathophysiology of depression and anxiety. We investigated interactions between antidepressants on SP-induced effects and their potential calcium-blocking activity in the isolated guinea pig ileum. All the antidepressants tested, except pargyline, moclobemide, mianserin, and reboxetine, were able to inhibit in a concentration-dependent manner the contraction induced by 100 nmol/L SP. Clomipramine, fluoxetine, maprotiline, and amitriptyline (all at 3 mumol/L) flattened the concentration-response curves to SP, resulting in a reduction of up to 59%, 63%, 32%, and 23%, respectively, of the maximum contractile effect. All the antidepressants tested (3 mumol/L), except pargyline, moclobemide, and mianserin, produced a rightward parallel shift of the concentration-response curve to CaCl2. The L-type selective calcium blocker nifedipine and the T-type selective mibefradil showed similar behaviour against both agonists used, SP and CaCl2. The relative order of potency was nifedipine (pA2, 7.6 +/- 0.1) > clomipramine (pA2, 7.0 +/- 0.1) > fluoxetine (pKB, 6.5 +/- 0.1) = mibefradil (pKB, 6.6 +/- 0.1) > amitriptyline (pKB, 6.3 +/- 0.1) = maprotiline (pKB, 6.2 +/- 0.1) > fluvoxamine (pKB, 5.9 +/- 0.1). The data reported in the present study suggest that the antidepressants tested did not behave as competitive antagonists versus NK1-receptor subtypes, but their inhibitory action seems to be related to their calcium-blocking properties.     

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.     

Antidepressant Utilization and Suicide in Europe: An Ecological Multi-National Study

Background

Research concerning the association between use of antidepressants and incidence of suicide has yielded inconsistent results and is the subject of considerable controversy. The first aim is to describe trends in the use of antidepressants and rates of suicide in Europe, adjusted for gross domestic product, alcohol consumption, unemployment, and divorce. The second aim is to explore if any observed reduction in the rate of suicide in different European countries preceded the trend for increased use of antidepressants.

Methods

Data were obtained for 29 European countries between 1980 and 2009. Pearson correlations were used to explore the direction and magnitude of associations. Generalized linear mixed models and Poisson regression distribution were used to clarify the effects of antidepressants on suicide rates, while an autoregressive adjusted model was used to test the interaction between antidepressant utilization and suicide over two time periods: 1980–1994 and 1995–2009.

Findings

An inverse correlation was observed in all countries between recorded Standardised Death Rate (SDR) for suicide and antidepressant Defined Daily Dosage (DDD), with the exception of Portugal. Variability was marked in the association between suicide and alcohol, unemployment and divorce, with countries depicting either a positive or a negative correlation with the SDR for suicide. Every unit increase in DDD of an antidepressant per 1000 people per day, adjusted for these confounding factors, reduces the SDR by 0.088. The correlation between DDD and suicide related SDR was negative in both time periods considered, albeit more pronounced between 1980 and 1994.

Conclusions

Suicide rates have tended to decrease more in European countries where there has been a greater increase in the use of antidepressants. These findings underline the importance of the appropriate use of antidepressants as part of routine care for people diagnosed with depression, therefore reducing the risk of suicide.     

Treatment of rapid cycling bipolar disorders

Rapid cycling (RC) bipolar disorder is defined as four or more affective episodes within one year. RC bipolar disorder constitutes one of the most difficult forms of the illness to treat effectively. According to several studies, RC bipolar patients have more severe symptoms than non-rapid cycling bipolar patients. Most studies indicate that only 10% to 20% of patients with bipolar disorders experience rapid cycling, but this is of great concern to psychiatrists because of its association with treatment refractoriness. Second generation antipsychotics are increasingly being used in the treatment of bipolar disorder. A first step in the management of rapid-cycling bipolar disorder is the thorough assessment of possible medications or environmental factors that may destabilize the disorder and contribute to the recurrence of episodes, increasing cycle frequency, or both. All currently approved antidepressant drugs pose some risk of mood destabilization, but the risk is highest for tricyclic antidepressants. Discontinuation of antidepressants should be the first step in the management of RC patients.     

Comparison of the Effects of Antidepressants and Their Metabolites on Reuptake of Biogenic Amines and on Receptor Binding

1. The present survey compares the effects of antidepressants and their principal metabolites on reuptake of biogenic amines and on receptor binding. The following antidepressants were included in the study: the tricyclic antidepressants amitriptyline, dothiepin, and lofepramine and the atypical antidepressant bupropion, which all have considerable market shares in the UK and/or US markets; the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; and the recently approved antidepressants venlafaxine and nefazodone.2. Amitriptyline has similar in vitro reuptake inhibitory potencies for 5-HT and NA, whereas the metabolite nortriptyline is preferentially a NA reuptake inhibitor. Both amitriptyline and nortriptyline are also 5-HT₂ receptor antagonists.3. Dothiepin has equipotent 5-HT and NA reuptake inhibitory activity, whereas northiaden shows a slight selectivity for NA reuptake inhibition. Dothiepin and northiaden are also 5-HT₂ receptor antagonists. The slow elimination rate of northiaden (36–46 hr) compared to dothiepin (14–24 hr) suggests that northiaden contributes significantly to the therapeutic effect of dothiepin.4. Lofepramine is extensively metabolized to desipramine. Desipramine plays an important role in the antidepressant activity of lofepramine, as the plasma elimination half-life of lofepramine (4–6 hr) is much shorter than that of desipramine (24 hr). Both compounds are potent and selective inhibitors of NA reuptake.5. The five approved SSRIs, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, are potent 5-HT reuptake inhibitors, and the demethyl metabolites, norfluoxetine, demethylsertraline, and demethylcitalopram, also show selectivity. Paroxetine and sertraline are the most potent inhibitors of 5-HT reuptake, whereas citalopram is the most selective. Fluoxetine is the least selective and the metabolite of fluoxetine, norfluoxetine, is a more selective and more potent 5-HT reuptake inhibitor than the parent compound and has an extremely long half-life (7–15 compared to 1–3 days). Thus the metabolite plays an important role for the therapeutic effect of fluoxetine. Fluoxetine is also a 5-HT_2C receptor antagonist. Demethylsertraline is a weaker and less selective 5-HT reuptake inhibitor in vitro than sertraline, but demethylsertraline has a very long half-life (62–104 hr) compared to the parent compound (24 hr) and it might play a role in the therapeutic effects of sertraline. Demethylcitalopram has about a 10 times lower 5-HT reuptake inhibitory potency in vitro than citalopram, and the elimination half-lives are approximately 1.5 and 2 days, respectively.6. Bupropion and hydroxybupropion are weak inhibitors of biogenic amine reuptake. The mechanisms of action responsible for the clinical effects of bupropion are not fully understood, but it has been suggested that both dopaminergic and noradrenergic components play a role and that the hydroxybupropion metabolite contributes significantly to the antidepressant activity.7. Venlafaxine and O-demethylvenlafaxine are weak inhibitors of 5-HT and NA reuptake, and the selectivity ratios are close to one. O-Demethylvenlafaxine is eliminated more slowly than venlafaxine (plasma half-lives of 5 and 11 hr, respectively), and it is likely that it contributes to the overall therapeutic effect of venlafaxin.8. Nefazodone and -hydroxynefazodone are equipotent 5-HT and NA reuptake inhibitors. Both compounds are also 5-HT₂ receptor antagonists. Both parent compound and metabolite have short elimination half-lives.     

Controlled trial of trimipramine,monoamine oxidase inhibitors,and combined treatment in depressed outpatients.

A study was carried out in which 135 mildly or moderately depressed outpatients were randomly allocated to one of five groups receiving six weeks'' treatment weith antidepressant drugs. The groups received a tricyclic antidepressant (trimipramine; mean dose 106 mg at night) or a monoamine oxidase inhibitor (MAOI) (phenelzine or isocarboxazid; mean doses 45 and 32 mg/day respectively), or a combination of the two (phenelzine plus trimipramine or isocarboxazid plus trimipramine). Various scales were used to measure depression before and at one, three, and six weeks of treatment, and results were assessed blindly. The tricyclic antidepressant was found to be consistently superior to the MAOIs and the combined treatments. Some differential indicators of response to the various antidepressants were found--for example, patients with initial complaints of dizziness, suicidal ideas, irritability, and insomnia and a longer duration of illness were more likely to respond to trimipramine--but these were of only modest significance. Side effects were not troublesome in any group. It is concluded that neither MAOIs nor MAOIs combined with tricyclic antidepressants are the treatment of first choice in unselected outpatients with mild or moderate depression.     

The inhibition of GLUT1 glucose transport and cytochalasin B binding activity by tricyclic antidepressants

Under normal metabolic conditions glucose is an important energy source for the mammalian brain. Positron Emission Tomography studies of the central nervous system have demonstrated that tricyclic antidepressant medications alter cerebral metabolic function. The mode by which these drugs perturb metabolism is unknown. In the present study the interactions of tricyclic antidepressants with the GLUT1 glucose transport protein is examined. Amitriptyline, nortriptyline, desipramine, and imipramine all inhibit the influx of 3-O-methyl glucose into resealed erythrocytes. This inhibition is observed with drug concentrations in the millimolar range. All four antidepressants also noncompetitively displace cytochalasin B binding to GLUT1. The K(I) for this displacement ranges from 0.56 to 1.43 millimolar. This value is in a range greater than that associated with clinical doses and this effect may not be directly applicable to side effects observed with normal use. The observed interaction of these drugs with GLUT1 may reflect an affinity for other glucose-transport or glucose-binding proteins, and may possibly contribute to tricyclic antidepressant toxicity.     

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

Antidepressants are commonly used in the treatment of anxiety and depression, medical conditions that affect approximately 17-20% of the population. The clinical effects of antidepressants take several weeks to manifest, suggesting that these drugs induce adaptive changes in brain structures affected by anxiety and depression. In order to develop shorter-acting and more effective drugs for the treatment of anxiety and depression, it is important to understand how antidepressants bring about their beneficial effects. Recent reports suggest that antidepressants can induce neurogenesis in the adult brain, although the mechanisms involved are not clearly understood. In this review, we describe the different neurotransmitter systems that are affected by anxiety and depression and how they are modulated by antidepressant treatment with a focus on signaling molecules and pathways that are activated during neurotransmitter receptor induced neurogenesis.     

Antidepressant drugs: imipramine, mianserin and trazodone

The advent of newer antidepressant drugs (second generation) during the past two decades has provided an alternative to the use of tricyclic antidepressants in the alleviation of depression. These antidepressants have not been proven to be superior in the therapy of depression to the tricyclic antidepressants but they have been reported to cause fewer cardiac effects. Most of the reported adverse cardiac reactions elicited by antidepressant drugs are based on observations from clinical studies. The possible underlying mechanisms by which these adverse reactions arise have for the large part been proposed on the basis of clinical findings which have been extrapolated back to the known pharmacological actions of such drugs. There is a paucity of hard experimental data in this respect.     

St John's wort for depression--an overview and meta-analysis of randomised clinical trials.

OBJECTIVE--To investigate if extracts of Hypericum perforatum (St John''s wort) are more effective than placebo in the treatment of depression, are as effective as standard antidepressive treatment, and have fewer side effects than standard antidepressant drugs. DESIGN--Systematic review and meta-analysis of trials revealed by searches. TRIALS--23 randomised trials including a total of 1757 outpatients with mainly mild or moderately severe depressive disorders: 15 (14 testing single preparations and one a combination with other plant extracts) were placebo controlled, and eight (six testing single preparations and two combinations) compared hypericum with another drug treatment. MAIN OUTCOME MEASURES--A pooled estimate of the responder rate ratio (responder rate in treatment group/responder rate in control group), and numbers of patients reporting and dropping out for side effects. RESULTS--Hypericum extracts were significantly superior to placebo (ratio = 2.67; 95% confidence interval 1.78 to 4.01) and similarly effective as standard antidepressants (single preparations 1.10; 0.93 to 1.31, combinations 1.52; 0.78 to 2.94). There were two (0.8%) drop outs for side effects with hypericum and seven (3.0%) with standard antidepressant drugs. Side effects occurred in 50 (19.8%) patients on hypericum and 84 (52.8%) patients on standard antidepressants. CONCLUSION--There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe depressive disorders. Further studies comparing extracts with standard antidepressants in well defined groups of patients and comparing different extracts and doses are needed.     

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.     

Effects of long-term treatment of rats with antidepressants on adrenergic-receptor sensitivity in cerebral cortex: Structure activity study

The effects of 20 tricyclic and 12 chemically unrelated ‘atypical’ antidepressant drugs on the noradrenaline (NA) receptor coupled adenylate cyclase system were investigated in slices of the rat cerebral cortex. While no changes occurred after a single dose, 14 tricyclic compounds down-regulated the receptor system when administered for 9 days. Six tricyclic antidepressants (trimipramine, butriptyline, noxiptyline, doxepine, dosulepine, propizepine) failed to desensitize the NA sensitive adenylate cyclase although some were potent inhibitors of the neuronal uptake of NA. Using the two optically active enantiomers of oxaprotiline inhibition of NA uptake was observed with the (+)-enantiomer while the (?)-enantiomer had only weak inhibitory potency. However, in contrast to published data, both enantiomers and the racemate administered at 30 mg/kg for 9 days did down-regulate the NA receptor coupled adenylate cyclase. Therefore, the experiments were repeated with Sprague-Dawley rats from a different supplier. Now, data published earlier were reproducible, only the racemate and the (+)-enantiomer of oxaprotiline being significantly active on the desensitization of the NA sensitive adenylate cyclase. Using F-344, Long Evans and Wistar rats significant differences were found in the response of the adrenoceptor coupled adenylate cyclase to a 9 day treatment with 30 mg/kg imipramine. Although some of the atypical antidepressants are potent inhibitors of the biogenic amine uptake systems none of these compounds lead to statistically significant changes of the NA stimulated cAMP formation after a 9-day treatment period. Only with the NA uptake inhibitor tandamine and with the serotonin uptake inhibitors zimelidine and fluoxetine a trend toward adrenergic down-regulation was recognized. Using enantiomers of mianserin only the (?)-isomer which is a poor NA uptake inhibitor, was slightly active. It thus appears that the therapeutic action of antidepressant drugs cannot generally be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system. Variabilities in pharmacokinetics and in NA sensitivity of the cAMP generating system in various rat strains and possibly in different animal species may be important factors determining whether β-receptor down-regulation will occur during chronic treatment with antidepressant drugs.     

Antidepressants and pregnancy: risks and benefits for the mother and child

Depression, anxiety disorders, anorexia nervosa and bulimia, all indications for antidepressant use, are common disorders in women of childbearing age. Nevertheless, antidepressant use during the gestational period remains a controversial topic. Given that 50 % of pregnancies are unplanned, the safety of antidepressants during the first trimester of pregnancy, a critical period for foetal development, has become a major public health concern. Until now, most studies suggest that physicians may often under-prescribe or discontinue antidepressants at the time of conception and during pregnancy. This may be a consequence of the concern over the safety of these agents in pregnant women and the risks they may pose to the foetus. In fact, recent studies and warnings from Health Canada and the US Food and Drug Administration have reinforced this uncertainty regarding the adverse effects of antidepressant use on the foetus. On the other hand, discontinuation of antidepressant use during pregnancy was also recently associated with maternal relapse of depression and withdrawal symptoms, which is not optimal for the mother and her foetus. Consequently, women who wish to become pregnant and who suffer from psychiatric disorders are faced with the difficult task of deciding whether to continue or discontinue their antidepressant during pregnancy. At this time, it appears important to take into account all evidence-based data to evaluate the risks/benefits of using antidepressants during the gestational period in order to help mothers make the best choice for themselves, and their infants.     

抗抑郁新药的研究与开发

随着社会经济高速发展,人们面临的社会竞争和心理压力加大,导致抑郁症逐渐成为现代社会的常见及高发疾病,所以临床上对 抗抑郁新药的需求日益增长。概述近年来欧美上市的抗抑郁新药和目前临床III期在研的部分抗抑郁小分子药物的合成工艺及临床研究进 展。