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Escitalopram vs TAK-653
Introduction
For patients with major depressive disorder (MDD) or other types of depression, there are medications that can help in stabilizing mood and managing symptoms by altering the concentrations of neurotransmitters in the brain. Escitalopram and TAK-653 are two such drugs considered for depression, each affecting different neurotransmitter systems to provide mood-stabilizing effects. Escitalopram is a selective serotonin reuptake inhibitor (SSRI), which works by increasing levels of serotonin–a neurotransmitter involved in mood, learning, reward, and memory, among other functions. TAK-653 is an investigational drug (not yet approved by the FDA but being studied in clinical trials) that acts as a positive allosteric modulator of AMPA receptors, influencing glutamate signaling pathways to exert rapid antidepressant effects. Both medications aim to offer reflief for patients suffering from depression, but they differ significantly due to their regulatory status and their distinct mechanisms of action. These drugs will be compared across various metrics in this article, including their history, mechanisms of action, side effects, and cost.
What is Escitalopram?
Escitalopram (commonly known by the brand names Lexapro and Cipralex) is an SSRI antidepressant that was first approved by the FDA in 2002. Escitalopram works by increasing levels of serotonin in the brain, similarly to other SSRIs, but is known for its particularly high selectivity for serotonin relative to norepinephrine, making it one of the best-tolerated SSRIs. Escitalopram is the purified S-enantiomer of citalopram (one of two 'mirror image' molecules), another SSRI that has been in use since 1998. Escitalopram appears to be mildly more effective and tolerable than citalopram, and appears to be the safest SSRI antidepressant for children and adolescents.
TAK-653, on the other hand, is a novel investigational drug that targets depression symptoms through an entirely different mechanism. TAK-653 acts as a positive allosteric modulator at AMPA receptors, increasing the effect of glutamate, which plays a key role in neuroplasticity (the creation of new connections between neurons). Early studies suggest that TAK-653 may offer rapid antidepressant effects with potentially fewer side effects than traditional antidepressant medications due to this unique mechanism of action, but it is currently not available to patients outside of clinical trials, where it is being investigated for treatment-resistant depression
What conditions is Escitalopram approved to treat?
Escitalopram is approved for the treatment of various conditions, including:
- Major depressive disorder (MDD), in both adults and adolescents
- Generalized anxiety disorder (GAD) in adults
- Additional indications in the EU and UK (but not the US) include social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder
How does Escitalopram help with these illnesses?
Escitalopram helps to manage depression and anxiety by increasing the amount of serotonin available in the synapses of the brain. It achieves this by inhibiting the reuptake of serotonin into neurons, thereby allowing higher levels of this neurotransmitter to remain active for longer periods. Serotonin plays a crucial role in regulating mood, cognition, memory, sleep patterns, appetite, and body temperature, among other functions. Low levels of serotonin appear to be implicated in depression, and thus escitalopram can mitigate depressive symptoms and help stabilize mood.
Over the long-term, reducing the reuptake of serotonin can lead to downregulation (decreased availability) of 5-HT1A receptors, which has been linked to improved passive stress tolerance and decreased negativity bias, which describes the tendency to overemphasize or focus on things perceived as 'negative'—a common characteristic of depressive and anxiety disorders. The same mechanism of action results in effects that can also alleviate anxiety. An ideal strategy for treating depression would have patienta take antidepressants to support them in making positive changes to their lifestyle and habits, alongside therapy. The patient could then eventually be taken off of the antidepressant medication, and continue to be supported by the positive effects of healthy lifestyle habits and the new thought patterns and behaviors they were able to introduce through therapy.
What is TAK-653?
TAK-653 is a novel investigational drug that targets depression symptoms through an entirely different mechanism than SSRIs and most other antidepressants. TAK-653 acts as a positive allosteric modulator at AMPA receptors, increasing the effect of their natural substrate, glutamate. Glutamate is the most abundant excitatory neurotransmitter in the human central nervous system, and it plays a key role in learning and memory, amongst other functions, due to its importance in synaptic neuroplasticity (creating new connections between neurons). AMPA receptors are one type of glutamate receptor, which are specifically involved in fast excitation.
TAK-653 is still under clinical investigation, and thus has not yet received approval for general use. Early studies suggest that TAK-653 may offer rapid antidepressant effects with potentially fewer side effects than traditional antidepressant medications due to its unique action on glutamatergic signaling pathways as opposed to the monoamine systems that are the focus of SSRIs like escitalopram. This novel mechanism may offer advantages for patients who do not respond adequately to conventional antidepressants like escitalopram, or who find their side effects unmanageable. SSRIs share common side effects that include nausea, insomnia, and sexual dysfunction, and the unique mechanism of action of TAK-653 means it does not have the same side effects.
The development of TAK-653 represents ongoing innovation in finding more effective treatments for depression through diverse pharmacological approaches. Its potential for fast-acting relief from depressive symptoms is of particular interest since SSRIs tend to take 2 to 4 weeks for their full therapeutic effects to be realized. TAK-653 is currently only accessible through clinical trials, wherein it is being studied for treatment-resistant depression.
What conditions is TAK-653 approved to treat?
TAK-653 is being investigated for its potential benefit in treating the following conditions:
- Major depressive disorder (MDD)
- Treatment-resistant depression (TRD)
TAK-653 is not yet available for general use. Potential FDA approval will depend on the results of clinical studies that are currently ongoing.
How does TAK-653 help with these illnesses?
While most classical antidepressants focus on modulating the activity of serotonin (and/or norepinephrine and dopamine), TAK-653 is unique in that it targets glutamate pathways. Glutamate is the most abundant excitatory neurotransmitter and is involved in a wide range of processes in the central nervous system, including learning and memory, and it also modulates the action of other neurotransmitters. Abnormal glutamate signaling has been implicated in several psychiatric disorders, including depression.
TAK-653 works by modulating the activity of AMPA receptors, which are one of three (or four, depending on the definition) main types of glutamate receptors. AMPA receptors are crucial for fast synaptic transmission in the central nervous system, wherein signals are sent in fractions of a millisecond. Specifically, TAK-653 works as a positive allosteric modulator (PAM) at AMPA receptors. This means it binds to the receptor at a different site than glutamate, but this binding increases the activity of (potentiates) glutamate at its natural site on the receptor. Even more specifically, it does so by slowing the rate of desensitization and internalization (think of it like the 'deactivation') of the receptor. By enhancing the function of AMPA receptors, TAK-653 appears to exhibit a fast-acting alleviation of depressive symptoms. TAK-653 is currently still an nvestigational drug, meaning it's being studied in clinical trials and has not yet been approved for general use. However, its distinct mechanism of action and rapid action explain its potential as an interesting option for people who don't respond well to SSRIs or other classical antidepressants, or for those who find the side effects of such drugs to be too unpleasant.
How effective are escitalopram and TAK-653?
Escitalopram (Lexapro, Cipralex) and TAK-653 are both designed for treating depression, but the two drugs differ significantly in their mechanisms of action and clinical use.
Escitalopram is an established and commonly prescribed antidepressant of the selective serotonin reuptake inhibitor (SSRI) class, approved for use in the US by the FDA in 2002. It works by increasing levels of the neurotransmitter serotonin in the brain to help improve mood. TAK-653 is an investigational drug, meaning it is currently being studied in clinical trials and is not yet approved for general use. TAK-653 acts by enhancing glutamate neurotransmission to achieve antidepressant effects.
The clinical effectiveness of escitalopram has been studied over more than 2 decades, through numerous clinical trials as well as real-world evidence from clinical practice. These studies have demonstrated its efficacy in alleviating symptoms of depression, and suggest that its safety profile may be somewhat favorable compared to those of other SSRIs. Escitalopram is typically regarded as the safest option for treating depression in adolescents and children. It shares the common side effects of SSRIs, which can include weight gain, sexual dysfunction, and trouble sleeping, although it is generally well-tolerated.
TAK-653 represents an exciting advancement in pharmacotherapy for depression due to its unique mode of action targeting glutamatergic pathways. Glutamate is an abundant neurotransmitter that's involved in over 90% of synaptic connections in the human brain. It plays a crucial role in neural plasticity, which describes the formation of new neural connections and pathways in the brain–a key process in learning, memory, and making long-term changes in the structure of the brian. Glutamate is also increasingly being recognized for its involvement in the pathology of depression, which diverges from the traditional focus on the predominant role of serotonin in depression. Early-phase clinical trials have showd promising results regarding TAK-653’s rapid onset of action against depressive symptoms, without causing some of the common SSRI-related side effects like sexual dysfunction or weight gain. However, as it's still being studied, comprehensive data confirming its long-term safety and efficacy is not yet available, and it's not yet available for prescription.
While SSRIs like escitalopram stand strong as first-line treatments for depression given their successful history of use, novel options such as TAK-653 may eventually offer valuable alternatives, especially for individuals who do not respond adequately to or cannot tolerate the side effects of SSRIs and other classical antidepressants. TAK-653 also represents novel therapeutic directions in depression research, which may change the way depression is understood and treated.
At what dose is escitalopram typically prescribed?
Oral dosages of escitalopram typically range from 10–20 mg/day for adults, with 10 mg/day being sufficient for treating major depressive disorder in most people. Adolescents may begin treatment with a lower dosage of 5–10 mg/day, depending on the severity of symptoms and their clinical response. Dose can be increased after several weeks if the response is inadequate. However, the maximum dosage of escitalopram is 20 mg/day. Always consult a healthcare provider before making any changes to prescribed medications or dosages.
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At what dose is TAK-653 typically prescribed?
In clinical studies, TAK-653 has been administered at doses ranging from 0.5 mg/day (not expected to have any effect) to 6 mg/day (expected to elicit therapeutic effect).
If TAK-653 is eventually approved by the FDA for depression treatment, the dosage (or dosage range) will be specified along with other relevant information for both doctors and patients.
What are the most common side effects of escitalopram?
Like most other SSRIs, escitalopram has possible side effects that include:
- Indigestion
- Anxiety or nervousness
- Insomnia (trouble sleeping) or somnolence (drowsiness)
- Tremors (unintentional trembling or shaking)
- Decreased appetite
- Nausea and dyspepsia (burning sensation, discomfort, or pain in the upper abdomen)
- Diarrhea
- Dry mouth
- Sweating more than usual
- Decreased libido (sex drive) and other sexual problems such as delayed ejaculation in men and inability to reach orgasm
- Rash
- Feeling tired or fatigued
- Abnormal dreams
- Asthenia (general weakness and fatigue)
- Pharyngitis, indicated by inflammation at back of the throat, or sinusitis, indicated by congestion and headaches
Are there any potential serious side effects for escitalopram?
Escitalopram also carries a risk of rare but more serious side effects, which would require immediate medical attention to avoid potential complications. Signs of a possible severe adverse reaction can include:
- Increased frequency or severity of thoughts about suicide or self-harm
- Signs of allergic reaction or severe skin reaction: hives, difficulty breathing, swelling in your face or throat, fever, sore throat, burning eyes, skin pain, and/or a red or purple skin rash with blistering and peeling
- Blurred vision, tunnel vision, eye pain or swelling, seeing halos around lights
- A fast or pounding heartbeat, fluttering sesnsation in the chest, shortness of breath, sudden dizziness (feeling like you might pass out)
- Signs of low sodium levels in the body: headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady
- Severe nervous system reactions such as very stiff muscles (rigidity), high fever (hyperthermia), sweating profusely (diaphoresis), confusion (delirium), a fast/uneven heartbeat (tachycardia/arrhythmias), and/or tremors/shakiness
- Serotonin syndrome, indicated by signs such as restlessness, hallucinations, fever, fast heartbeat, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea
What are the most common side effects of TAK-653?
In early clinical trials, TAK-653 was generally well-tolerated at a dose of 6 mg/day, but was related to the following mild side effects (in order of decreasing frequency):
- Somnolence (sleepiness)
- Headache
- Nasopharyngitis
- Oropharyngeal pain
- Diarrhea
- Seasonal allergy
- Fatigue
Are there any potential serious side effects for TAK-653?
Long-term safety data has not yet been collected for TAK-653 as it is still in clinical trials. Serious adverse effects, if any exist, may not be known until further studies are completed on a greater number of participants. During early-phase trials, no severe adverse events were reported, thus indicating a good safety profile based of TAK-653 on limited preliminary evidence.
Contraindications for escitalopram and TAK-653
Both escitalopram and TAK-653, like many other antidepressant medications, have the potential to exacerbate symptoms of depression in some individuals. If you notice your depression worsening or experience an increase in suicidal thoughts, ideation, or behavior while taking either of these medications, it is crucial to seek immediate medical attention.
Escitalopram should not be taken by anyone currently taking or who has recently taken monoamine oxidase inhibitors (MAOIs), such as phenelzine (Nargil), tranylcypromine (Parnate), or selegiline (Eldepryl, Emsam), as this can lead to a dangerous condition known as serotonin syndrome. A wash-out period of at least 14 days is required after last taking any MAOIs before starting treatment with escitalopram.
Contraindications for TAK-653 are not yet clear, but will be shared as part of the safety data if TAK-653 receives FDA approval. If you are considering taking part in a clinical trial for TAK-653, the principal investigator will make sure it's safe for you as part of your eligibilty assessment.
Always inform your physician about all the medications you are taking, as well as herbal and dietary supplements and vitamins, to avoid potentially harmful interactions.
How much do Escitalopram and TAK-653 cost?
For the brand name versions of escitalopram, Lexapro or Cipralex, costs average around $450 for a one-month supply (30 tablets x 10 mg each), which works out to approximately $15/day.
TAK-653 is an investigational drug is and not yet commercially available, so ni pricing data is available. If it is eventually approved, it is safe to assume it will only be available as a brand-name version for the first 15–20 years due to patent rights.
Escitalopram is available in generic form, and is significantly cheaper than Lexapro or Cipralex. A pack of 30 tablets can range from $4 to about $15, working out to just $0.13 to $0.50 per day of treatment. Generic drugs are molecularly equivalent to their brand-name counterparts, and can offer significant cost savings for patients paying out-of-pocket.
Popularity of escitalopram and TAK-653
Escitalopram, in both generic form and as brand names such as Lexapro and Cipralex, was prescribed over 30 million times in the US in 2021, making it one of the most commonly used SSRI medications. Its usage has been relatively stable over recent years due to its efficacy and favorable side effect profile.
TAK-653 is a novel investigational drug that is still in clinical trials, and is thus not yet available for prescription. If results are promising, TAK-653 may become an important addition to the options available for managing depression, potentially offering relief where other treatments have failed due to its unique mechanism of action.
Conclusion
Escitalopram is a well-established selective serotonin reuptake inhibitor (SSRI) antidepressant that increases the availability of serotonin in the brain to alleviate depressive symptoms. It has a long history of use and is generally well-tolerated, explaining its position as one of the most popular first-line therapies for depression. It is widely available in generic form, making it more accessible for patients paying out of pocket. Common side effects are similar to those of most SSRIs, and include nausea, insomnia or drowsiness (depending on the individual’s reaction), sexual dysfunction, and weight gain.
TAK-653 is an investigational drug that acts as a positive allosteric modulator at AMPA receptors to enhance glutamate neurotransmission, which represents a novel approach to treating depression. TAK-653 remains under clinical investigation, and its efficacy and safety profile will become clearer through ongoing studies. Early trials indicate good tolerability, and only mild side effects were reported.
TAK-653 represents exciting research into novel ways to treat depression, and its discovery is related to the emergence of ketamine as an effective fast-acting antidepressant that works on glutamate signalling rather than the monoamine neurotransmitter pathways targeted by typical antidepressants. Ongoing research may uncover new ways of understanding depression, and the goal is to offer a wider variety of treatment options to patients suffering from this condition. For the time being, there is a wide array of effective antidepressants available, such as escitalopram, offering most patients good pharmacological treatment options to help manage their symptoms.
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Refrences
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