Mechanism of action of antidepressant drugs: importance of genetically modified mice in the pharmacological in vivo approach

The main hypothesis regarding the mechanism of action of antidepressant drugs is monoaminergic and mainly involves two neurotransmitters, serotonin and noradrenaline. Despite the well-recognized therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs), some disadvantages still occur. For example, they often require 4-6 weeks to achieve clinical benefits in depressed patients. In the past, some molecules that could shorten this long delay of action have been identified. The role of presynaptic autoreceptors - the activation of which leads to an inhibitory feedback control on neurotransmitter synthesis and release - has been extensively studied for antidepressant effects. In our laboratory, we studied the combined effects of an SSRI and a serotonin autoreceptor antagonist of the 5-HT1B subtype using intracerebral in vivo microdialysis in awake, freely moving mice. Important information on SSRIs has been obtained by applying this technique to genetically modified animals, such as constitutive knockout (KO) mice lacking 5-HT1B receptors (5-HT1B KO) generated by homologous recombination: we compared the effects of a combined treatment on extracellular/intrasynaptic levels of serotonin in various nerve terminals area in wild-type control and KO mice. Thus, we found that indirect activation of 5-HT1B autoreceptors limits the effects of SSRIs on dialysate 5-HT levels at serotonergic nerve terminals such as the ventral hippocampus. The study of substance P (neurokinin 1 receptor [R-NK1]) offers another example of the use of KO mice in the development of a new class of antidepressant drugs. NK1 receptor antagonists may display anxiolytic/antidepressant-like properties. The lack of selective compounds for each tachykinin receptor subtype (R-NK 1, R-NK2 or R-NK3) and differences in their affinity between animal species have made R-NK1 KO mice a very useful experimental tool. In collaborative work we found that genetic (R-NK1 KO mice) or pharmacological (GR205171) blockade of R-NK1 is associated with several changes: the increase in cortical 5-HT outflow caused by systemic injection of paroxetine was 4- to 6-fold higher in freely moving R-NK1 KO mice than in wild-type controls. The constitutive lack of NK1 receptors is associated with a functional desensitization of somatodendritic 5-HT1A autoreceptors, resembling that induced by chronic treatment with SSRI antidepressants. These results highlight the link between a neurotransmitter (serotonin) and a neuropeptide (substance P). This genetic strategy allowed us to point out that multiple targets participate to the effects of classical antidepressant drugs within the brain. We hope that, soon, some mice lines (constitutive or tissue specific, conditional rescue mice having alterations of sleep/wakefulness and/or food intake, altered central serotonin and/or noradrenaline neurotransmission, deficit in neurotrophic factors, but increases in intrasynaptic concentrations of substance P) could be a relevant model of the physiopathology of depressive disorders, and could help us understand the appearance of some symptoms. These recent findings suggest that instead of being rejected, the monoaminergic hypothesis of depression should be improved, corrected and completed by studying the role of other neurotransmitter, neuromodulatory compounds (substance P, BDNF [brain-derived neurotrophic factor]). By doing so, it thus could be possible to improve antidepressant drug treatment, i.e. shorten their long delay of action and/or to decrease treatment resistance or improve its tolerance.     

Interest of using genetically manipulated mice as models of depression to evaluate antidepressant drugs activity: a review

Among the multiple possibilities to study human depressive disorders, animal models remain important preclinical tools. They allow the understanding of the mechanisms of action of antidepressant drugs. Primarily developed in rat, animal models of depression have been adapted to the mouse, an easy-to-use mammal with better genetic possibilities than rats. As an example, genetic manipulation of the serotoninergic 5-hydroxytryptamine-HT; (5-HT) system provided important opportunities to investigate the role of this monoamine in mood disorders. The contribution of either constitutive knockout (KO), tissue specific, or inducible KO mice and animal models in the current knowledge of the pathophysiology and treatment of depression is unanimously recognized. The phenotype of genetically manipulated animals is strongly influenced by both the genetic background of the animal as well as environmental factors. For these reasons, it is necessary to underline that KO mice have been generated on various genetic backgrounds, which strongly influence the behavioral and neurochemical responses to the tests. The present review will thus focus on KO mice lacking G protein-coupled monoaminergic receptors (e.g; 5-HT1B, 5-HT1A, and 5-HT4 receptors) and the 5-HT serotonin transporter, which is the main target of antidepressant drugs (or strategies). The importance of KO mice for neurotrophic factors, particularly for brain-derived neurotrophic factor and its main receptor displaying a tyrosine kinase activity, will also be addressed to illustrate the fact that in preclinical studies, combination of genetic manipulations with pharmacological ones should allow further progress in the field of neuropsychopharmacology.     

Antidepressants increase glial cell line-derived neurotrophic factor production through monoamine-independent activation of protein tyrosine kinase and extracellular signal-regulated kinase in glial cells

Recent studies show that neuronal and glial plasticity are important for therapeutic action of antidepressants. We previously reported that antidepressants increase glial cell line-derived neurotrophic factor (GDNF) production in rat C6 glioma cells (C6 cells). Here, we found that amitriptyline, a tricyclic antidepressant, increased both GDNF mRNA expression and release, which were selectively and completely inhibited by mitogen-activated protein kinase kinase inhibitors. Indeed, treatment of amitriptyline rapidly increased extracellular signal-regulated kinase (ERK) activity, as well as p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase activities. Furthermore, different classes of antidepressants also rapidly increased ERK activity. The extent of acute ERK activation and GDNF release were significantly correlated to each other in individual antidepressants, suggesting an important role of acute ERK activation in GDNF production. Furthermore, antidepressants increased the acute ERK activation and GDNF mRNA expression in normal human astrocytes as well as C6 cells. Although 5-hydroxytryptamine (serotonin) (5-HT), but not noradrenaline or dopamine, increased ERK activation and GDNF release via 5-HT2A receptors, ketanserin, a 5-HT2A receptor antagonist, did not have any effect on the amitriptyline-induced ERK activation. Thus, GDNF production by amitriptyline was independent of monoamine. Both of the amitriptyline-induced ERK activation and GDNF mRNA expression were blocked by genistein, a general protein tyrosine kinase (PTK) inhibitor. Actually, we found that amitriptyline acutely increased phosphorylation levels of several phosphotyrosine-containing proteins. Taken together, these findings indicate that ERK activation through PTK regulates antidepressant-induced GDNF production and that the GDNF production in glial cells may be a novel action of the antidepressant, which is independent of monoamine.     

Antidepressant treatment of chronic tension-type headache: a comparison between fluoxetine and desipramine

Amitriptyline, which is a noradrenaline reuptake and 5-HT reuptake inhibitor, has an established role in the management of chronic tension-type headaches. In a single-blind study, patients with chronic tension-type headache were randomized to either fluoxetine 20 mg (a selective 5-HT reuptake inhibitor) or desipramine 75 mg (a selective noradrenaline reuptake inhibitor) and followed for 12 weeks to compare the effectiveness of the two drugs in improving headache, and to assess whether pain control is related to changes in depression. Patients were evaluated at weekly intervals on an analog pain-rating scale and at 4-weekly intervals on the Montgomery and Asberg Depression Rating Scale (MADRS), the MOS general health status questionnaire (SF36), the Hospital Anxiety and Depression Scale (HADS), and a side effects checklist. Eighteen patients were randomized to take fluoxetine and 19 to take desipramine. Of the 25 patients who completed the trial, 12 were on fluoxetine and 13 were on desipramine. There was no significant difference between the two groups at baseline nor in change of pain; reduction in use of analgesic medication; nor change in the HADS, MADRS, or SF36 scores at 12 weeks, but 72% of patients who completed the study improved, and this improvement almost exactly mirrored the improvement on the MADRS. The results from this trial are compatible with the notion that the beneficial effect of antidepressants in chronic tension-type headache is indirect, mediated by an effect on depression, and not more,dependent on serotonin reuptake inhibition than noradrenaline reuptake inhibition.     

Treatment of anxiety and depression: medicinal plants in retrospect

Anxiety and depression are complex heterogeneous psychiatric disorders and leading causes of disability worldwide. This review summarizes reports on the fundamentals, prevalence, diagnosis, neurobiology, advancement in treatment of these diseases and preclinical assessment of botanicals. This review was conducted through bibliographic investigation of scientific journals, books, electronic sources, unpublished theses and electronic medium such as ScienceDirect and PubMed. A number of the first‐line drugs (benzodiazepine, azapirone, antidepressant tricyclics, monoamine oxidase inhibitors, serotonin selective reuptake inhibitors, noradrenaline reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors, etc.) for the treatment of these psychiatric disorders are products of serendipitous discoveries. Inspite of the numerous classes of drugs that are available for the treatment of anxiety and depression, full remission has remained elusive. The emerging clinical cases have shown increasing interests among health practitioners and patients in phytomedicine. The development of anxiolytic and antidepressant drugs of plant origin takes advantage of multidisciplinary approach including but not limited to ethnopharmacological survey (careful investigation of folkloric application of medicinal plant), phytochemical and pharmacological studies. The selection of a suitable plant for a pharmacological study is a basic and very important step. Relevant clues to achieving this step include traditional use, chemical composition, toxicity, randomized selection or a combination of several criteria. Medicinal plants have been and continue to be a rich source of biomolecule with therapeutic values for the treatment of anxiety and depression.     

Review of pharmacological efficacies and side effects of antidepressants

We reviewed the pharmacological efficacies and side effects of antidepressants. Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs) are most popularly prescribed for anxiety disorders as well as mild or moderate depression. These drugs have less orthostatic, cognitive, cardiovascular, and anticholinergic side effects. Tricyclic antidepressants are still important for treating severe depression, and mianserin and trazodone are useful for treating delirium. Clinicians should select antidepressants considering their pharmacologic profiles and avoiding adverse effects.     

Current biochemical hypotheses of endogenous depression

In this short introductory review the current important working hypotheses of depression, the noradrenaline and serotonin hypotheses, are described and critically evaluated. Anticholinergic properties, co-modulation of various transmitters by different neuropeptides, great variations in the influence on the "re-uptake" mechanism for noradrenaline and serotonin with no effect by novel antidepressants like iprindole, mianserin and clenbuterol and variability to either stimulate or block receptor systems (alpha 1-, alpha 2-, beta-, serotonin-, dopamine-, adenylate cyclase dependent-, histaminergic receptors and possibly others) might further indicate a complex pathobiochemical background to depression. More recently, a unified hypothesis has been presented on the basis of subsensitivity of the noradrenaline-sensitive adenylate cyclase and/or down regulation of the number of beta-receptors by antidepressants of otherwise different pharmacological properties. Furthermore, another hypothesis, the "brain area specific imbalance of neurotransmitter systems" tries to combine current knowledge of the biochemistry of depressive disorders, the different pharmacological profiles of antidepressants and the divergence of symptomatology in depressed patients. Since antidepressant activity of drugs is dependent on the functional state of pre- and postsynaptic neurotransmission it seems essential to define the basal activity of such systems in vivo and to study the functional change after therapy. Furthermore, phenomena like adaptation and tolerance must be considered in future research in order to get more detailed information about pathobiochemical processes causing depression.     

Status of treatment of depression.

BACKGROUND: Depression is a common and highly treatable disorder, with most patients returning to predepression levels of functioning. Patients with depression must be carefully assessed for the presence of comorbid psychiatric or medical disorders, as well as psychosocial stresses. METHODS: I present a clinical overview, supported by pertinent literature, of currently available treatments of depression, with an emphasis on primary practice. RESULTS: Beyond diagnosis, treatment consists of patient education and support, evaluation of suicide risk, and treatment of symptoms with antidepressant medication, psychotherapy, or both. A multitude of antidepressants are available, including cyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and newer, more receptor-specific agents such as nefazodone, venlafaxine, and mirtazapine. These are reviewed with a focus on mechanism of action, side-effect profile, and clinical use. CONCLUSIONS: All available antidepressants have been found effective in the treatment of mild-to-moderate depression. Choice of agent is based primarily on side-effect profile. For patients with an atypical pattern of symptoms, SSRIs or MAOIs may be the most useful. Patients with severe depression or melancholic symptoms may respond better to tricyclic antidepressants, venlafaxine, or mirtazapine.     

Tolerability and safety of fluvoxamine and other antidepressants

Selective serotonin [5-hydroxytryptamine (5-HT)] reuptake inhibitors (SSRIs) and the 5-HT noradrenaline reuptake inhibitor, venlafaxine, are mainstays in treatment for depression. The highly specific actions of SSRIs of enhancing serotonergic neurotransmission appears to explain their benefit, while lack of direct actions on other neurotransmitter systems is responsible for their superior safety profile compared with tricyclic antidepressants. Although SSRIs (and venlafaxine) have similar adverse effects, certain differences are emerging. Fluvoxamine may have fewer effects on sexual dysfunction and sleep pattern. SSRIs have a cardiovascular safety profile superior to that of tricyclic antidepressants for patients with cardiovascular disease; fluvoxamine is safe in patients with cardiovascular disease and in the elderly. A discontinuation syndrome may develop upon abrupt SSRI cessation. SSRIs are more tolerable than tricyclic antidepressants in overdose, and there is no conclusive evidence to suggest that they are associated with an increased risk of suicide. Although the literature suggests that there are no clinically significant differences in efficacy amongst SSRIs, treatment decisions need to be based on considerations such as patient acceptability, response history and toxicity.     

Development of newer antidepressant

The development of antidepressant started from 1950's and it is based on monoamine hypothesis. Antidepressants enhance monoamine, such as serotonin, nor adrenaline and dopamine neurotransmission by blockade of monoamine transporter or monoamine oxydase. The antidepressants under clinical trials enhance those monoamine in various combinations. The development of newer antidepressants is still on pre-clinical trials. Those candidates such as neurotrophic factors and neuropeptides may show antidepressant effect without monoamine hypothesis and those are expected to overcome the limitation of existing antidepressant.     

度洛西汀临床应用现状

度洛西汀是一种5-羟色胺和去甲肾上腺素双重再吸收抑制剂,通过抑制5-羟色胺和去甲肾上腺素双重再摄取,增强中枢5-羟色胺和去甲肾上腺素神经递质的功能而发挥抗抑郁作用,同时提高5-羟色胺和去甲肾上腺素两种神经递质在调控情感和对疼痛敏感程度方面的作用,提高机体对疼痛的耐受力。无明显的抗胆碱能、抗肾上腺素能、抗组织胺能活性的不良反应,具有相对良性的心血管作用谱,药物之间相互作用少。对伴有或不伴有躯体症状的抑郁症、精神分裂症后抑郁、躯体形式障碍、广泛性焦虑症等均取得了较好的治疗作用。     

Chronic pain treatment with antidepressants--metaanalysis

Both preclinical and clinical evidence support the usefulness of antidepressants in chronic pain treatment. Monoamine uptake inhibitors influence the neurotransmissions of noradrenaline (NA) and/or serotonin (5-HT); their effect on nociception is thought to take place predominantly within the spinal cord. Antidepressant drugs seem to differ in their properties as analgesics and as thymoleptics. The present work is aimed at correlating the special mechanism of action of antidepressants in diminishing nocicepetion with the pharmacological profile of these drugs in clinical pain treatment. From a preclinical, experimental point of view, it can be expected, that mixed type uptake blockers should be superior to selective NA or 5-HT uptake inhibitors. The analgesic profile of antidepressants was established by a metaanalysis of clinical trials on the effect of these drugs, given alone or in combination with other analgetics, in chronic pain syndromes. 57 Clinical trials were separated into 5 groups according to their scientific quality: [1] placebo-controlled double-blind studies with high power; [2] placebo-controlled double-blind studies with low power; [3-4] open controlled studies or studies with historical controls; [5] case reports. A study was positive if the tested antidepressant was more effective than placebo or the compared drug or seemed beneficial with respect to the interval of its previous absence. The most effective antidepressants in chronic pain treatment only included unselective monoamine reuptake inhibitors in the following rank order: amitriptyline > clomipramine > or = desipramine > or = imipramine > or = doxepin. A statement about the appropriate dosage of these drugs in chronic pain treatment, however, must wait for properly conducted dose finding studies which include the measurement of plasma concentrations.     

Intracellular signal transduction mediated via 5-HT and NA receptors

The present brief review was discussed about the intracellular signal transduction mediated via 5-HT and NA receptors focussing on the mechanism of antidepressants. Recent studies demonstrated that long-term antidepressant treatments resulted in activation of cAMP pathway at several levels including CREB(cAMP response element-binding protein) and BDNF(brain-derived neurotrophic factor). These pathways are elevated via 5-HT and/or NA receptors which directly couple to the cAMP system(5-HT4,6,7 receptors or beta adrenoceptors), or via receptors that lead to activation of Ca(2+)-dependent protein kinase(5-HT2 receptors or alpha 1 adrenoceptors). Such factors could be common targets for many different type of antidepressants. Elucidation of the signal transduction mediated via 5-HT and/or NA receptors, therefore, provide significant information understanding the pathophysiology of depression.     

Pharmacological profile of binedaline, a new antidepressant drug

The interactions of binedaline (binodaline), a new antidepressant drug, and its main metabolites with neurotransmitter receptors and monoamine uptake sites were studied. In receptor binding assays, binedaline was compared to amitriptyline, imipramine, maprotiline and mianserin. Unlike these drugs binedaline did not show any significant affinity for an alpha adrenergic, muscarinic cholinergic, histamine H1 or serotonin2 (5-HT2) receptors. Binedaline and desmethylbinedaline were potent inhibitors of the uptake of norepinephrine in synaptosomes from rat cerebral cortex (Ki = 25 and 29 nM, respectively). Binedaline also inhibited 5-HT uptake with a weak affinity (Ki = 847 nM) but was inactive as an inhibitor of dopamine uptake in synaptosomes from rat striatum (Ki greater than 2 microM). No specific binding was found using [3H]binedaline. After 2 weeks of daily administration of binedaline (20 mg/kg i.p.), the number of beta adrenergic recognition sites labeled with [3H]CGP 12177 remained constant in rat forebrain, as did 5-HT2 receptors and benzodiazepine receptors. In contrast a prolonged treatment with maprotiline (20 mg/kg i.p.) increased the apparent Kd value of [3H]CGP 12177 by 43% and the apparent maximal binding value of [3H]RO 15-1788 by 20% as compared to control. Our results indicate that binedaline is comparable to a tricyclic antidepressant drug in inhibiting the norepinephrine uptake but, however, it is devoid of affinity for neurotransmitter receptors. This probably explains why this drug does not induce the classical side effects of tricyclic antidepressant drugs. These results also suggest that a reduction in beta adrenergic, 5-HT2 or benzodiazepine receptors is not always related to an antidepressant chronic treatment.     

Efficacy of venlafaxine for the long term treatment of chronic pain with associated major depressive disorder

BACKGROUND: This was an open-label, single-center study of the long-term efficacy and effectiveness of venlafaxine extended release (XR) in the treatment of chronic pain and depression in outpatients. All patients have been diagnosed with major depressive disorder (MDD) of various types, with or without chronic pain, and had previously failed treatment with either tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs). METHODS: Efficacy of treatment was determined using the 21-item Hamilton Rating Scale for Depression (HAMD-21), the Visual Analogue Scale (VAS) for the evaluation of pain, and a 12-item quality of life scale (QOL). Patients were treated in an unblended open trial for 1 year with 150 mg or more of venlafaxine XR once daily. RESULTS: After 1 year of treatment, 21-item Hamilton Rating Scale for Depression, Visual Analogue Scale, and quality of life scores were significantly improved from permanent baseline scores. CONCLUSION: These data show long-term efficacy and effectiveness of venlafaxine XR, a serotonin (5-HT) and norepinephrine (NE) and dopamine (DA) reuptake inhibitor antidepressant agent, having analgesic properties.     

The neurobiology of antidepressants.

Raising neurotransmitter levels is only one means by which antidepressants act. The activity of modern drugs appears to readjust the balance between serotonin and noradrenaline by more fundamental means. Likely mechanisms include correction of the diminished sensitivity and numbers of specific serotonin and noradrenaline receptors found in depression. Also responsible may be changes in the normal pattern of movements of these transmitters across the synaptic membranes within the diffuse modulatory systems. It is possible that by increasing the serotonin levels these drugs may increase neurogenesis, suggesting that neuronal losses may be a fundamental cause of the symptoms.     

New drugs in the treatment of depression and schizophrenia

Pharmacological agents are important in the treatment of many patients with major depression or psychotic illness. Antidepressant drugs such as the tricyclic antidepressants and non-selective monoamine oxidase inhibitors are associated with significant adverse effects, especially in overdose. Newer antidepressants include selective serotonin reuptake inhibitors and reversible, selective monoamine oxidase inhibitors. These new drugs are clinically effective and have greatly improved side effect profiles, being considerably safer in overdose than older agents. In the treatment of psychosis, risperidone and clozapine represent clinical advances and are less likely to induce adverse neurological effects than existing neuroleptic agents.     

Pharmacogenomics and antidepressant drugs

While antidepressant pharmacotherapy is an effective treatment of depression, it still is hampered by a delayed time of onset of clinical improvement and a series of side effects. Moreover, a substantial group of patients has only limited response or fails to respond at all. One source accounting for these variations are genetic differences as currently analysed by single nucleotide polymorphisms (SNP) mapping. In recent years a number of pharmacogenetic studies on antidepressant drugs have been published. So far they mostly focused on metabolizing enzymes of the cytochrome P450 (CYP) families and genes within the monoaminergic system with compelling evidence for an effect of CYP2D6 polymorphisms on antidepressant drug plasma levels and of a serotonin transporter promoter polymorphism on clinical response to a specific class of antidepressants, the selective serotonin reuptake inhibitors. It is clear, however, that other candidate systems have to be considered in the pharmacogenetics of antidepressant drugs, such as neuropeptidergic systems, the hypothalamus-pituitary adrenal (HPA) axis and neurotrophic systems. There is recent evidence that polymorphisms in genes regulating the HPA axis have an important impact on response to antidepressants. These studies mark the beginning of an emerging standard SNP profiling system that ultimately allows identifying the right drug for the right patient at the right time.     

The management challenges of chronic pain: the role of antidepressants

Chronic pain is both difficult for patients to tolerate and for clinicians to treat effectively. It differs from other types of pain in etiology and impact, which in turn affects the duration and modalities of treatment options. Forty years of research have confirmed the efficacy of antidepressant agents in the management of chronic pain, yet these agents are used inadequately. A significant amount of evidence supports the use of the traditional tricyclic antidepressants (TCAs) in the management of chronic pain, but because of their acute synaptic effects on multiple, nontherapeutic receptor systems, they are associated with numerous undesirable side effects. The newer selective serotonin reuptake inhibitors (SSRIs) have, comparatively, only serotonin-receptor-mediated side effects. These agents have not been thoroughly studied in the treatment of chronic pain. Moreover, because SSRIs impact reuptake of only one monoamine system, it is plausible that they may be less efficacious than the TCAs in treating chronic pain. Venlafaxine, the first agent in the new class of serotonin (5-HT)-norepinephrine (NE) reuptake inhibitors, is unique because it inhibits reuptake of both 5-HT and NE (and to a lesser extent dopamine), as do some of the TCAs; however, it accomplishes this without affecting other nontherapeutic receptors. Venlafaxine is at least as effective as the TCAs, but is more tolerable, because it lacks the receptor-mediated side effects common to the TCAs. The unique characteristics of venlafaxine, including minimal cytochrome P-450 drug interaction, may make it a particularly useful antidepressant in the adjunctive treatment of chronic pain.     

The symptoms, neurobiology, and current pharmacological treatment of depression.

Depression as a medical disorder increasingly is being recognized and treated. The mood of an individual with major depression is often described as sad, hopeless, or discouraged, and there are many physical symptoms associated with depression. Pharmacologic treatments for depression have advanced greatly since the development of the first therapies, monoamine oxidase inhibitors (MAOIs). Many medications, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs), currently are available to help combat this health problem. Newer medications have eliminated many of the side effects associated with older therapies, and treatments in development are designed with the goal of further improving on efficacy while eliminating side effects.