Neuropharmacology Series: Lifting the Fog: Mechanisms of Action of Antidepressants

Foreword

Diseases and disorders that affect the nervous system are becoming more prevalent. In part due to aging populations, the demand for effective treatments has never been more critical. Significant research has been devoted to the development of drugs to treat these conditions. However, the unique challenges posed by the nervous system make medication development a formidable task. One of the primary complexities in treating nervous system disorders is the Blood-Brain Barrier (BBB), a selective membrane that regulates the movement of molecules and ions between the blood and the brain. The BBB protects the brain from infection but makes it difficult for medications to reach their site of action in the nervous system. The first challenge to any neuropharmacology treatments, therefore, is finding drugs that can cross the BBB. This article series will detail the strategies used by different medications to cross this barrier and exert their effects on the nervous system.

Neuropharmacology emerged 50 years ago as a specialised branch of pharmacology that deals with drugs which influence the nervous system to treat or improve psychiatric and neurological diseases. The Neuropharmacology series will explore six key categories of neuropharmacological drugs: antidepressants, anxiolytics, antipsychotics, antiepileptics, treatments for Parkinson’s and Alzheimer’s, and drugs of abuse. The Neuroscience series aims to provide valuable insights into the intricacies of drug development for nervous system disorders, offering a comprehensive understanding of the challenges faced and breakthroughs achieved. Reading this series will help readers better understand the mechanisms, nuances, and prospects of treatments for psychiatric and neurological conditions.

This series is divided into six articles including:

1. Neuropharmacology Series: Lifting the Fog: Mechanisms of Action of Antidepressants

2. Neuropharmacology Series: Calm in Chaos: Exploring Anxiolytics

3. Neuropharmacology Series: Balancing the Mind with Antipsychotics

4. Neuropharmacology Series: Seizing Control: The Power of Antiepileptics

5. Neuropharmacology Series: Unravelling the Future of Parkinson’s and Alzheimer’s Treatments

6. Neuropharmacology Series: Beyond the High: The Complexities of Drugs of Abuse.

Neuropharmacology Series: Lifting the Fog: Mechanisms of Action of Antidepressants

Depression and its related mood disorders can cast a fog over the life of a person affected by this condition. Beyond sadness, depression infiltrates every aspect of a patient’s life, affecting their mood, sleep patterns, and overall emotional well-being, as well as functional impairment and drastically increased risk of suicide. The effects of depression are far-reaching and stretch outside of the person suffering from this condition, causing family distress and conflict, added health care costs, and productivity losses, increased health care costs, and productivity losses, as well as impaired cognitive development of newborns in cases of post-partum depression (Goldman et al., 1999).  

The symptoms of depression can vary greatly between individuals, and not all those with depression will display the same symptoms. Some of the main symptoms are low mood, loss of interest or pleasure, decreased energy, and persistent fatigue. In order to obtain a formal diagnosis of depression, a patient must display at least two of these core symptoms. These symptoms can be improved through lifestyle changes, social support and psychological therapy, but many of those suffering from depression may need antidepressant medication. Antidepressants play a pivotal role in alleviating these symptoms, though the precise mechanism of action and pharmacology of every type of antidepressant is not known. Pharmacological interventions may not truly cure depression, though patients can enter remission from this condition, where they are free from all symptoms, following these treatments (Paykel, 2008). In order to understand the mechanisms of antidepressants, the pathophysiology of depression, particularly the role of neurotransmitters, must be examined.

It is notable that depression is not always treated with antidepressants, or indeed any drugs. Non-drug therapy, including psychotherapy, electroconvulsive therapy or a combination of non-drug and drug treatments have been effective for some patients. There are also transient, or short-lived, subtypes of depression where spontaneous recovery can occur, and antidepressant treatment is not required. In such cases, treatment utilizing placebos have sometimes proven successful. However, more severe types of depression, there is a clear preference among clinicians for use of an antidepressant drug (Bayes & Parker, 2019).

Figure 1: Symptoms of Depression (Unknown, n.d.).

Pathophysiology of Depression

Although the exact cause of depression is unknown, many hypotheses have been put forward to explain the pathophysiology of this condition and how it can develop in individuals. Some of the most robust hypotheses implicate neurotransmitter imbalance as a potential cause of depression. For example, the Monoamine Hypothesis of depression, the prevailing hypothesis to explain depression, proposes that depression symptoms are caused by a deficiency of monoaminergic transmitters (Bondy, 2002). Monoaminergic transmitters are also known as neuromodulators. This group includes dopamine, norepinephrine, and serotonin, which are associated with emotion, mood, motivation and fatigue (Jiang et al., 2022). The hypothesis suggests that the lack of monoaminergic transmission is due to a lack of availability of these neurotransmitters in the synapse. As transmission of a signal from one neuron to the next relies on neurotransmitters carrying the signal across the synaptic synapse, a lack of neurotransmitters means that the signal is not transmitted. This disruption in signaling is believed to cause, or at least significantly contribute to, depression (Bondy, 2002).

There are several stages of synaptic transmission, including synthesis and storage of neurotransmitters, and their regulated release into the synaptic cleft, and the reuptake of neurotransmitters after they have transmitted their message. Reuptake is a vital stage of synaptic transmission where transporter proteins from the presynaptic cell inactivate the spent neurotransmitters and return them to the neuron they came from, where they are metabolized and recycled by enzymes. Effective synaptic signaling relies on rapid deactivation and removing of neurotransmitters to control the duration of neurotransmitter stimulation of postsynaptic receptors (Richerson & Wu, 2003). As reduced monoamine function is believed to lead to depression, most antidepressants work by effecting synaptic transmission of these neurotransmitters to improve the signal and alleviate the symptoms of depression. The key target of antidepressants like selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) is neurotransmitter reuptake. By effecting reuptake, these antidepressants can control the level of neurotransmitters available in the synapse, and so control the duration of synaptic signals (Andrade & Rao, 2010).

Figure 2: Healthy and Depressed Synapses (Unknown, n.d.).

Mechanisms of Action

Depression is a complex and heterogenous disorder. As such, there is no single mechanism of action that encompasses all antidepressants. Three main mechanisms of action have been identified that are used by antidepressants to restore monoamine balance: reuptake inhibition, receptor blockade, and inhibition of enzymes that degrade monoamines. The outcome of these mechanisms is the same: increasing the concentration of the monoamines serotonin and norepinephrine at postsynaptic receptors (Artigas et al., 2002).

Antidepressants can be classified into three groups, based on their mechanism of action: monoamine oxidase inhibitors, α2-adrenoceptor antagonists and reuptake inhibitors. Monoamine oxidase inhibitors (e.g., moclobemide) inhibit the degradation of monoamines, and α2-adrenoceptor antagonists (e.g mirtazapine) act at specific receptors to affect the monoamine system (Westenberg, 1999). Mirtazapine is an atypical antidepressant that inhibits presynaptic α2-adrenergic receptors in the brain to increase the release of both serotonin and norepinephrine through dual modes of action to equally increase the levels of both of these monoamines. This drug is used to treat major depressive disorder, following SSRI treatment. Since mirtazapine also has sedative, antiemetic, anxiolytic, and appetite stimulant effects, it is also used to treat insomnia (Jilani et al., 2023). Reuptake inhibitors work by inhibiting monoamine reuptake at the synaptic cleft. This type of antidepressant can be further divided into three categories: SSRIs (e.g., paroxetine) which selectively reuptake serotonin, selective NRIs (e.g., reboxetine) that selectively reuptake norepinephrine, and SNRIs (e.g., venlafaxine) which inhibit the reuptake of both serotonin and norepinephrine. These reuptake inhibitors differ based on their relative potency to block serotonin and norepinephrine uptake site, with SSRIs being the most potent (Westenberg, 1999).

Figure 3: Types of Antidepressants (Paingeeri, n.d.).

The First Antidepressants

Some of the earliest pharmaceutical treatments for depression are monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), which were first used in the 1950s. Their mood-elevating effects led to the discovery of the relation of brain chemistry and mood (Ferguson, 2001). MAOIs inhibit the enzyme monoamine oxidase (MAO), which is found in the membranes of mitochondria. This enzyme normally inactivates neuronal dopamine, serotonin, and norepinephrine to end a neuronal signal. By inhibiting MAO, MAOIs increased the synaptic availability of these monoamines to strengthen the signal, which elevates mood. There are two isomers of MAO, MAO-A and MAO-B. Non-selective MAOIs can inhibit both isomers while selective MAOIs inhibit one or the other, however as MAO is found in brain regions rich in serotonergic, norepinephrinergic and dopaminergic neurons, it is thought MAO-A inhibition is required to tangibly affect depression symptoms (Thase, 2012).

Many psychiatric medications have been discovered by chance, as was the case with MAOIs. When the tuberculosis drug iproniazid was found to treat depression symptoms in patients, it was more widely prescribed under the name Marsilid as a depression treatment. Eventually, it was discovered that iproniazid inhibited MAO, accounting for this drug´s antidepressant effects. In the first year after the discovery of the antidepression properties of this drug, it was used to treat more than 400,000 patients (Shulman et al., 2013). Similarly, the first TCA, imipramine, was discovered accidentally during phenothiazine antipsychotic research (Bodkin, 2007). Although iproniazid was eventually removed from the market due to toxicity, other MAOIs have since been developed. MAOIs have been used as antidepressants for decades (Shulman et al., 2013).

Although MAOIs and TCAs were effective in treating depression, there were significant drawbacks to these drugs. Many MAOIs were found to be toxic with prolonged use. Additionally, MAOIs are irreversible and will permanently bind to MAO. As the life of this enzyme lasts for 14-28 days, the effects of MAOIs last for at least 14 days before new enzymes are generated and normal MAO activity can return (Thase, 2012). There is also a great risk to the patient from adverse side effects. The most common side effect associated with MAOIs is hypotension (low blood pressure), and adverse interactions with other drugs and food. Co-exposure of MAOIs to substances with indirectly acting sympathomimetic properties can be very dangerous. If certain foods or drugs are taken concurrently with MAOIs, there is a risk of dangerous hypertensive and hyperpyretic crises occurring which requires α-blockade treatment. To prevent this, drug prescription is strictly monitored by the physician, and patients are advised to not consume foods with high-tyramine levels (Lippman & Nash, 1990). TCAs also had drawbacks, with a narrow therapeutic index and, when given in high doses, they can slow intraventricular conduction to such an extent that it blocks the heart, causing seizures and even death (Ferguson, 2001). As a result, there was a need to develop safer, better tolerated and more specified alternatives (Ferguson, 2001). Antidepressants may also interfere with hepatic enzymatic pathways, such as SSRIs which inhibit CYP2D6. As this enzyme is involved in the metabolism of other drugs, this inhibition could elevate levels of these drugs in the body, which can cause further knock-on effects (Bayes & Parker, 2019). A study by Thase et al. (1995) suggests that TCAs and MAOIs are more effective at treating certain groups of patients, and different types of depression. They found that TCAs were more effective at treating severe depression than MAOIs. This study also showed a significant difference in efficacy of these drugs in inpatients vs outpatients, where MAOIs were more successful than TCAs in treating outpatients. Clomipramine, a TCA, has been shown to be more effective in treating patients that were hospitalised from depression than the SSRIs citalopram and paroxetine, as well as the reversible MAOI moclobemide (Bayes & Parker, 2019).

Figure 4: MAO Inhibitors (Unknown, n.d.).

For decades, TCAs and MAOIs were the only antidepressants clinically available. TCAs are the precursors of SSRIs and SNRIs, and their basic mechanisms of action are the same: inhibiting reuptake of monoamine neurotransmitters in the synaptic cleft (Bodkin, 2007). SSRIs and SNRIs are also more selective than MAOIs, and so have fewer side effects (Artigas et al., 2002). Since the development of SSRIs, prescription rates of MAOIs and TCAs has fallen drastically worldwide (Chockalingam et al., 2018). TCAs are usually classified as either SNRIs or selective NRIs. Their main therapeutic activity is through their effects on synaptic reuptake mechanisms, but TCAs have multiple other pharmacologic properties and so are classified as non-selective agents (Westenberg, 1999). Although the first antidepressants have largely been replaced with newer treatments, MAOIs still have a place in treating depression. Many patients who experience more challenging mood disorders have benefitted from these drugs. Depression sub-types such as treatment-resistant depression, atypical depression and bipolar depression that are not effectively treated with newer treatments have been successfully treated with MOAIs (Shulman et al., 2013). Furthermore, some TCAs, such as clomipramine have been shown to be more effective at treating severe depression than SSRIs (Artigas et al., 2002). Despite this, the negative association of early treatments for depression has made doctors and clinicians reluctant to prescribe these medications (Shulman et al., 2013).

Current Antidepressants

Antidepressants like TCAs have a 50-75% response rate for moderate to severe depression, compared to a 25-33% response rate for placebo treatment. The difference between antidepressant drugs and placebo response rates is much less for less severe types of depression. Meta-analyses into MDD have suggested that this is due to reduced levels of response to placebos in severely depressed patients, rather than any increased responsiveness to medication (Bayes & Parker, 2019). Patients with mild to moderate depression respond to most classes of antidepressants equally, while those with more severe MDD have a more varied response. The variation in response can be between particular drugs, even those that are of the same antidepressant classification. For example, escitalopram has shown a greater likelihood of patients entering remission from depression than its fellow SSRIs fluoxetine, sertraline, paroxetine and citalopram (Bayes & Parker, 2019).

Figure 5: Antidepressant Classes (Unknown, n.d.).

SSRIs and SNRIs

SSRIs and SNRIs were developed in the 1980s and 90s to treat depression in line with the monoamine hypothesis of depression, by increasing monoamine availability at the synapse. Serotonin reuptake is blocked by SSRIs, and SNRIs block reuptake of both serotonin and norepinephrine (Artigas et al., 2002). These drugs have similar mechanisms of action and primarily target serotonin transporters (SERT) or norepinephrine transporter (NET) to affect reuptake of the affiliated monoamines. While these two types of drugs are similar, individual drugs within these classifications have different levels of selectivity and affinity for their primary targets, SERT and/or NET. As well as these primary targets, these drugs have an affinity for binding with secondary receptors and transporter targets at certain doses. For example paroxetine, an SSRI, also shows affinity for NET while fluoxetine has affinity for SERT. Furthermore, some SNRIs show a higher potnecy for SERT or NET binding. For example, venlafaxine binds with more affinity to SERT. Duloxetine, however, shows more balanced binding and appears to inhibit SERT and NET equally. These distinct pharmacological properties can impact clinical efficacy, and even tolerability, which should be taken into account when prescribing particular medicines (Dale et al., 2015).

Although they are similar, SSRIs and SNRIs have different advantages and disadvantages and the use of one over the other depends on the specific requirements of the patient. While SSRIs only effect serotonin reuptake, SNRIs inhibit both serotonin and norepinephrine. As a result, SNRIs have a wider therapeutic range than SSRIs and have been used to treat neuropathic pain, as well as other chronic pain conditions. SNRIs also tend to affect the patient more quickly and have less adverse effects in the event of an overdose (Aljassem et al., 2022). On the other hand, SSRIs are the most prescribed antidepressant, as they have a high success rate with fewer side effects than other treatments (Hall, 2006). In particular, SSRIs have fewer effects on adrenergic, cholinergic, and histaminergic receptors than TCAs or MAOIs, and have little to no effect on dopamine or norepinephrine, with the exception of the SSRI paroxetine. This leads to fewer side effects that have been commonly reported with other antidepressants, such as xerostomia (dry mouth), sedation, constipation, urinary retention, and cognitive impairments (Chu & Wadhwa, 2023). Citalopram and fluoxetine are two commonly prescribed SSRIs. They have similar effectiveness and have shown only mild side effects. However, fluoxetine has a longer half-life, as well as potential adverse drug-drug interactions than citalopram (Coulombe et al., 2020).

Figure 6: SERT and NET (Unknown, n.d.).

Little evidence has been found on whether there is any significant difference in the efficacy of SNRIs and SSRIs for treating depression and anxiety disorders, though one study by Papakostas et al. (2007) did find that SNRIs were sightly more efficacious than SSRIs in treatment of MDD. Further research is needed to determine if this difference would be statistically significant within certain MDD sub-populations, or for specific symptoms of MDD. However, while SSRIs are generally ineffective in treating chronic pain, SNRIs can also be used to treat chronic pain, which is often associated with depression (Stahl et al., 2005). As SSRIs and SNRIs are more effective than less selective antidepression medications, this led to a greater understanding of the pathophysiology of depression, namely: that serotonin and norepinephrine play more significant roles in depression than other neurotransmitters (Artigas et al., 2002).

SNRIs

There are three major SNRI medications: venlafaxine, milnacipran, and duloxetine, which effectively treat depression, and a variety of anxiety disorders. Although all three drugs inhibit the reuptake of serotonin norepinephrine, each does so to a varying degree of selectivity. Milnacipran inhibits serotonin and norepinephrine reuptake equally, while duloxetine has a 10-fold selectivity for serotonin and venlafaxine has a 30-fold selectivity for serotonin. There are also differences in the tolerability of these three SNRIs. Venlafaxine is the least well-tolerated, and patients can experience dose-dependent cardiovascular issues, particularly hypertension, as well as serotonergic adverse effects, which includes nausea, sexual dysfunction and withdrawal symptoms. Duloxetine and milnacipran have been better tolerated and patients have experience little to no cardiovascular toxicity (Stahl et al., 2005).

Tailoring Treatment to Individuals

How depression presents can vary from patient to patient, and not all patients will display the same symptoms, or they can show different severity of symptoms. Due to the unique nature of depression in each individual, treatment of this condition should also be unique in order to give the patient the best possible outcome for this debilitating disorder (Bayes & Parker, 2019).

There are several variables for a clinician to consider when a prescribing depression treatment, including symptoms, severity, duration, whether the patient is taking other medications that may interact with an antidepressant, side effects and the characteristics of the drug itself. Furthermore, pharmaceutical company sponsorship and advertising can drastically influence prescription rates (Bayes & Parker, 2019). In a study by Coulombe et al. (2020), it was determined that patient characteristics, including age, sex, BMI, smoking status, any psychiatric disorders, anxiety, or prior psychiatric admissions, had a statistically significant effect on the efficacy of SSRIs. However, the study did find that these characteristics can affect the risk of a severe depression-related outcome (SDO). By examining such patient characteristics, clinicians can make more informed choice about which antidepressants should be used for specific patients and reduce the risk of SDOs.

Figure 7: SSRI (Kelley, n.d.).

Challenges & Future

Normally, Phase I drug development occurs following careful consideration of what is known about the drug target and the molecule under investigation to decide the approach to be taken to best treat a condition and develop drug efficiently and cost effectively. However, due to the lack of fundamental knowledge about the causes and pathophysiology of depression, antidepressant development faces a huge challenge when attempting to make new drugs. There are some early indicators that can be employed to indicate efficacy of a new drug, such as the Emotional Test Battery, EEG markers, and fMRI correlates of anhedonia, they are not yet fully incorporated into Phase I. By utilizing new measures to determine efficacy early on, researchers would have greater ability explore new hypotheses and develop better, viable antidepressants faster (Alexander & Preskorn, 2014).

Despite the advances in depression treatments through the modulation of monoaminergic neurotransmission, there are many clinical needs of depression treatment that remain unmet (Rosenzweig‐Lipson et al., 2007). One issue that can effect antidepressant efficacy is ensuring that these drugs reach their relevant targets in the brain in clinically sufficient doses. During the research phase of drug development of antidepressants, this has often not been investigated thoroughly. Drugs effecting the brain do often struggle to reach the brain through the Blood Brain Barrier (BBB) to have a significant effect on neurological conditions. In antidepressant research, there have been multiple instances where projects had to be terminated because drugs that were developed were not reaching brain targets at high enough concentrations to produce therapeutic effects. In order to avoid this issue in the future, all factors that may influence a drug´s effect in the brain, such as plasma exposure, target engagement and pharmacodynamic response, must be taken into consideration.  This integrated style of drug development is gaining popularity in modern drug development. This may lead to more successful neurological treatments in the future (Dale et al., 2015).

While antidepressant treatment can cause remission from depression, relapse can occur. While most treatment courses for acute depression are short-term or medium-term as standard, depression disorder is often, by nature, a long-term condition. This means that when a short or medium term treatment course ends, the patient may be at risk of a relapse into depression. Although continued treatment can prevent relapse in many patients, there are adverse effects associated with prolonged antidepressant usage. Clinical guidelines have recommended that antidepressant should continue to be administered for 4-6 months following an acute depressive episode, though this is not optimal for many patients. While some patients are more at risk of relapse than others, further trials are needed to establish the optimum length of therapy (Geddes et al., 2003).

Figure 8: Rates of Depression Relapse (Sigler, 2024).

Current antidepressants have shown great improvements in efficacy, a large number of patients are experiencing Treatment Resistant Depression (TRD) (Rosenzweig‐Lipson et al., 2007). TRD is a clinical term for a type of major depressive disorder that does not respond adequately to current antidepressant treatments. Thase and Rush (1997) developed a set of criteria for differentiating the levels of resistance in TRD patients. This model defines antidepressant treatment resistance into five stages, from complete lack of response to at least one antidepressant to failure to respond to multiple classes of antidepressant and to ECT (Rosenzweig‐Lipson et al., 2007). Although there is no official consensus on a definition for TRD, generally a failure of at least two different antidepressant treatments results in a TRD diagnosis. However, “pseudo-resistance” can also occur, where a patient appears to be resistant to antidepressants due to the prescription of suboptimal doses, or comorbidities of depression with personality disorders or substance abuse, can give the false appearance of TRD. There are many approaches to treating TRD, including traditional means such as lithium treatment and electroconvulsive therapy, as well as newer treatments such as Deep Brain Stimulation, and the use of psilocybin or anti-inflammatories to combat TRD. As depression can be debilitating for patients, their families and society, TRD presents further difficulties and an expensive, prolonged treatment, with little hope of relief. Further studies are required to better understand TRD as a condition distinct from depression before truly effective therapies can be developed (Voineskos et al., 2020).

Another challenge to antidepressant treatment are severe side effects associated with current treatments. The popularity of SSRIs in depression treatment has led to an increase in serotonin syndrome. Serotonin is an important neurotransmitter required for nerve and brain functions, and drugs that increase serotonin, including antidepressants, can alleviate serious conditions like depression. However, too much serotonin can negatively impact the body, effecting mood, memory, and digestion. Serotonin syndrome is an accumulation of serotonin in the body and is a drug reaction to medications designed to increase serotonin availability. Subsequently, serotonin syndrome can be a serious risk when taking antidepressants. Although this condition is rare, it can be very serious and lead to altered mental status, autonomic dysfunction, neuromuscular abnormalities, agitation, delirium, mydriasis, diaphoresis, hyperthermia, tachycardia, fluctuating blood pressure, mutism, tremor, rigidity, and even seizures and coma. Mild to moderate cases can usually resolve within 24 to 72 hours, though may last for several weeks. Severe cases can result in liver failure, adult respiratory distress syndrome and death if left untreated (Martin, 1996).

Improving response rates is still the major challenge for antidepressant research and drug development. Better response rates to antidepressants could be achieved by better understanding the biological mechanisms of depression. Although extensive research in human genetics is ongoing to identify biologically well-defined subpopulations of depression, they have so far been unsuccessful (Dale et al., 2015).

Figure 9: Serotonin Syndrome (Unknown, n.d.).

Conclusion

Depression and its related mood disorders present a multifaceted challenge that permeates every aspect of an individual's life. A variety of treatment options are used to combat depression, though the most utilised are antidepressants, due to their efficacy. As our understanding of the pathophysiology of depression, particularly the role of neurotransmitter imbalance, has grown new classes of antidepressants have been developed. From the earliest discoveries of monoamine oxidase inhibitors to the more recent innovations in selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, the landscape of antidepressant pharmacotherapy continues to evolve. With so many types of antidepressants available, there are many choices for clinicians to customize a patient’s treatment to give them the best possible outcome and optimize the relief of their depression symptoms. How this condition manifests itself can vary in different patients, and so the treatment of this condition cannot be "one size fits all". While SSRIs and SNRIs share similar mechanisms, the choice between the two often depends on individual factors and the specific nature of the mental health condition. Tailoring treatment to the patient's needs, considering factors such as side effects, comorbidities, and individual responses, is crucial in optimizing the effectiveness of antidepressant therapy.

Challenges persist in the future of depression treatment, from the need for more effective interventions for treatment-resistant depression, to the mitigation of severe side effects associated with current medications. Additionally, the quest for better response rates demonstrate the need for continued research into this condition, in order to find the best treatments for this debilitating disorder.  

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