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Fluoxetine vs Tianeptine

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For patients with major depressive disorder (MDD) or other types of depression, there are medications that can help stabilize mood and manage symptoms by modifying the concentrations of chemical messengers called neurotransmitters in the brain. Fluoxetine and tianeptine are two such drugs prescribed for depression, each representing different classes of medications that work through distinct mechanisms to achieve their therapeutic effects. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI), a common class of antidepressant medications which increase the levels of serotonin in the brain by preventing its reabsorption into neurons. Tianeptine has a unique, multi-faceted mechanism of action. It modulates activity of glutamate receptors and levels of brain-derived neurotrophic factor (BDNF), helping to improve neuroplasticity (the ability of neural networks in the brain to adapt and change) and potentially protecting against stress-induced changes to the brain. Tianeptine acts as an agonist of the mu-opioid receptors (MOR), which appears to be responsible for its antidepressive effects. It also slightly enhances the release of dopamine in certain brain areas. Both drugs offer relief from depressive symptoms, but do so by affecting different biochemical pathways in the brain. In this article, fluoxetine and tianeptine are put side-by-side to compare their mechanisms of action, clinical benefits, and side effects.

What is Fluoxetine?

Fluoxetine (commonly known by the brand name Prozac) was the first drug developed within the SSRI class of antidepressants, receiving FDA approval in 1987. Fluoxetine works by increasing levels of free serotonin in the brain by inhibiting (preventing) its reabsorption into neurons. This mechanism effectively "traps" serotonin in synaptic spaces for a longer time, and the increased levels of serotonin are thought to be responsible for alleviating symptoms of depression. Fluoxetine is selective for serotonin, with minimal effect on dopamine and norepinephrine. Fluoxetine is one of the most commonly prescribed antidepressants, alongside other SSRIs, citalopram and sertraline. Its side effect profile is similar to that of other SSRIs, including dry mouth, trouble sleeping, sexual side effects, neausea, indigestion, diarrhea, and skin rash.

What conditions is Fluoxetine approved to treat?

Fluoxetine is approved for the treatment of major depression and other psychiatric conditions:

  • Major depressive disorder (MDD), also known as unipolar depression, in adults and also in adolescents
  • Anxiety disorders
  • Bulimia nervosa
  • Obsessive-compulsive disorder (OCD)
  • Bulimia nervosa
  • Panic disorder, with or without agoraphobia

How does Fluoxetine help with these illnesses?

Fluoxetine (commonly known as Prozac) helps to manage depression by increasing the amount of serotonin available in the synapses of the brain. It achieves this by inhibiting the reuptake (reabsorption) of serotonin into neurons, thereby increasing its availability. Serotonin plays a crucial role in mood regulation, cognition, memory, sleep patterns, appetite control, and body temperature, among other functions. By enhancing levels of free serotonin, fluoxetine can help mitigate depressive symptoms and stabilize mood. Over the long term, this effect of fluoxetine (like other SSRIs) can lead to downregulation (decreased availability) of 5-HT1A receptors, which has been linked to improved passive stress tolerance and decreased negativity bias–the tendency to overemphasize or focus on things perceived as 'negative,' which is a characteristic of depressive and anxiety disorders. The same mechanism of action results in effects that can also alleviate anxiety and help manage symptoms of other psychiatric disorders like PTSD and OCD. An optimal strategy for treating depression leverages antidepressants to support patients in making positive changes to their lifestyle and habits, alongside therapy. Over the long-term, it may be possible for the patient to be taken off of antidepressant medications, and continue to be supported by the positive effects of healthy lifestyle habits and the changes to thought patterns and behaviors brought about through therapy.

What is Tianeptine?

Tianeptine, marketed internationally under several brand names including Stablon and Coaxil, is an atypical antidepressant, resembling the first class of antidepressants developed known as tricyclic antidepressants. Tianeptine is not approved by the FDA for use in the US, although it has circulated as an unregulated drug. It has a unique mechanism of action among antidepressant medications, acting primarily as a modulator of glutamate receptors. This effect is thought to account for its antidepressive and anxiolytic (anti-anxiety) effects. In addition, tianeptine appears to modulate neuroplasticity through its interactions with the glutamate system, which may also play a role in its therapeutic potential in treating depression by helping the brain rewire. It also acts as an agonist at mu-opioid receptors (MOR), which appears to boost its therapeutic action on glutamate pathways but also confers it with other effects and side effects related to this opioid activity.

Tianeptine has been approved for use in many countries in Asia and Europe since the 1980s, but was never approved in the US by the FDA. It is currently being investigated for treatment-resistant depression, but there are concerns over its abuse potential due to its activity as an opioid receptor agonist. This mechanism of action can also result in potentially severe withdrawal symptoms upon discontinuing the drug. Side effects can include constipation, dry mouth, headache, insomnia, nightmares, dizziness, nausea and abdominal pain, agitation, and anxiety or irritability. Due to its distinct classification and mechanism of action, its side effects differ significantly from those of SSRIs.

What conditions is tianeptine approved to treat?

Tianeptine is not approved as a medication for use in the US. In Asia and Europe, tianeptine has been used for the treatment of:

  • Major depressive disorder (MDD)
  • Anxiety disorders
  • Asthma
  • Irritable bowel syndrome (IBS)

How does Tianeptine help with these illnesses?

Tianeptine works primarily by modulating glutamate pathways, but is also an agonist at mu-opioid receptors and mildly (and indirectly) increases dopamine in certain regions of the brain. Together, these effects confer it with a unique profile in the treatment of depression, as well as PTSD and Parkinson's disease. It has significant anti-anxiety properties, and is generally free of the sedative and cardiovascular side effects common to SSRIs.

The fast-acting effect of tianeptine in depression has helped researchers understand more about depression, since it acts through an entirely different mechanism of action compared to the main classes of antidepressants. Through its action on glutamate systems, tianeptine appears to reduce depressive symptoms directly, but also appears to improve cognitive function, likely through an increase in neuroplasticity. In addition to its glutamatergic properties, tianeptine is an agonist at mu-opioid receptors, which are the same receptors activated by opiate painkillers such as morphine. This property may confer some added therapeutic benefit, as it leads to stimulation of the glutaminergic pathway. Mild enhancements of dopamine in the mesolimbic pathway have also been noted with tianeptine. Because of its uncommon structure, tianeptine has a unique therapeutic profile as well as a different set of side effects. It also has been reported to have a high potential for abuse, and to cause an uncomfortable withdrawal syndrome upon stopping the medication due to its opioid activity.

How effective are fluoxetine and tianeptine?

Both fluoxetine (Prozac) and tianeptine appear to be successful in treating depression, but they act via entirely different mechanisms. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI), while tianeptine influences opioid receptors and has glumatergic properties that modulate neuroplasticity. This fundamental difference means that these drugs may be prescribed under varying circumstances depending on the patient's specific needs and response to treatment. However, it's important to note that tianeptine is not currently FDA-approved for use in the US.

Fluoxetine is well-studied due to its long history of use and its status as one of the most widely prescribed antidepressants. It is generally well-tolerated, offering significant benefit in the treatment of major depressive disorder, anxiety disorders, and OCD, with side effects similar to those of many other SSRIs. Although fluoxetine is one of the most commonly used antidepressants, some of the side effects may be unpleasant or untolerable for certain patients, which could lead them to seek alternative medications.

Studies have suggested that tianeptine is comparable in efficacy to SSRIs for depression, and this has actually helped researchers better understand the biological mechanisms underlying depression. Since tianeptine does not increase serotonin levels, like the majority of common antidepressants, it has called into question the idea that low serotonin levels are responsible for depression. It also demonstrates some distinct advantages, such as having significant anti-anxiety effects, which is relevant because anxiety and depression are often related. It is generally well-tolerated, and does not carry a risk of some of the common problematic side effects of SSRIs such as sedation/drowsiness, sexual dysfunction, and weight gain. However, its action of mu opioid receptors means it has a high potential for abuse, and can cause withdrawal syndrome if treatment is stopped suddenly. Side effects can include dry mouth, constipation, headache, insomnia, nightmares, dizziness, nausea and abdominal pain, agitation, and anxiety or irritability. Tianeptine has been used for decades in many countries in Asia and Europe, but has only been used unofficially as an unregulated substance in the US. It is currently undergoing clinical trials to assess its effectiveness in treatment-resistant depression.

At what dose is fluoxetine typically prescribed?

Oral dosages of fluoxetine typically range from 20–80 mg/day, with many studies indicating that 20 mg/day is often sufficient for treating major depressive disorder in most adults. Children and adolescents may start at a lower dose of 10 mg/day, which can be increased by a healthcare professional after several weeks if the response is not adequate. The maximum dosage that should not be exceed under any circumstance is 80 mg/day. It's crucial to follow a physician's guidance and the prescribed dose closely when taking fluoxetine to ensure the safety and effectiveness of the treatment.

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At what dose is tianeptine typically prescribed?

Tianeptine treatment is generally started at a dosage of 12.5 mg up to three times per day, spaced evenly throughout the day (morning, noon, and evening). The total daily dose for treatment is typically 25 to 50 mg. Adjustments to the dosage may be considered under close medical supervision after considering the patient response. In contrast to the SSRI antidepressants, tianeptine can begin to take effect right away, providing quick relief from symptoms of depression and anxiety. With tianeptine, it’s crucial to adhere strictly to dosing guidelines due to the risk of dependence if misused and an uncomfortable withdrawl syndrome upon stopping the drug after taking higher doses.

What are the most common side effects of fluoxetine?

The common mild side effects of fluoxetine can include:

  • Anxiety
  • Nervousness
  • Anorexia
  • Insomnia
  • Somnolence (sleepiness/drowsiness)
  • Vasodilation (widening of the blood vessels, which can decrease blood pressure)
  • Weight gain
  • Asthenia (general weakness and fatigue)
  • Nausea, abdominal pain
  • Tremor
  • Constipation
  • Dry mouth
  • Sinusitis
  • Decreased libido (sex drive)
  • Blurred vision
  • Rash
  • Excessive sweating
  • Abnormal dreams
  • Symptoms resembling the flu, such as muscle aches and fever

While most of these side effects are usually mild, you should speak with your doctor about any and all side effects or changes to your health you notice, particularly during the first months of initiating treatment with fluoxetine (or any new medication).

Are there any potential serious side effects for fluoxetine?

Fluoxetine also carries a risk of rare but more serious side effects. If you notice any of the following symptoms, you should seek medical attention immediately as they could indicate a more severe adverse reaction:

  • Increase in thoughts about suicide or self-harm, or self-harming behaviors, particularly in young adults and teenagers
  • Allergic reactions or severe skin reactions, recognizable by symptoms such as hives, difficulty breathing, swelling in your face or throat, fever, sore throat, a burning sensation in the eyes, or a red or purple skin rash with blistering and peeling
  • Eye problems, such as blurred vision or tunnel vision, eye pain or swelling, or seeing halos around lights
  • Accelerated, abnormal, or pounding heartbeat, or a fluttering feeling in your chest
  • Sexual dysfunction that persists even after stopping treatment
  • Shortness of breath
  • Seizures
  • Sudden dizziness (feeling like you might pass out)
  • Symptoms of low sodium levels, such as: headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination/feeling unsteady
  • Serotonin syndrome, characterized by: agitation, increased body temperature, confusion, tremor, sweating, diarrhea

Patients should be monitored during the first weeks or months of treatment. If you experience any of the above side effects, seek emergency medical assistance.

What are the most common side effects for Tianeptine?

The common mild side effects of tianeptine can include:

  • Anxiety
  • Irritability
  • Insomnia
  • Somnolence (sleepiness/drowsiness)
  • Orthostatic hypotension (low blood pressure upon changing posture/position, which can lead to fainting/falls)
  • Dizziness
  • Weight gain
  • Heart palpitations
  • Asthenia (general weakness and fatigue)
  • Nausea, abdominal pain
  • Tremor
  • Hot flushes
  • Constipation
  • Problems with urination
  • Dry mouth
  • Decreased libido (sex drive)
  • Blurred vision
  • Rash
  • Excessive sweating
  • Abnormal dreams
  • Symptoms resembling the flu, such as muscle aches and fever
  • Euphoria

While most of these side effects are usually mild, you should speak with your doctor about any and all side effects or changes to your health you notice, particularly during the first months of initiating treatment with tianeptine (or any new medication).

Are there any potential serious side effects for Tianeptine?

It's important to watch out for potentially severe adverse reactions when using Tianeptine. The following side effects may be indicative of more serious issues, and warrant urgent medical attention to rule out further problems:

  • Signs of an allergic reaction such as hives, itching, fever, swollen glands, difficulty breathing or swelling in your face or throat
  • Seizures (convulsions); confusion and unusual changes in mood or behavior
  • Manic episode—racing thoughts, heightened energy levels, reckless behavior, extreme happiness or irritability coupled with excessive talking and severe sleep issues.
  • Liver problems, including hepatitis, indicated by yellowing of the skin/eyes (jaundice), abdominal pain on the upper right side, and/or dark-colored urine
  • Misuse or taking high doses of tianeptine can lead to dependence and withdrawal issues similar to other opioid medications. Do not take more than the prescribed dose, nor more often that you are prescribed.

It is possible to overdose on tianeptine, which can be fatal due to respiratory depression. Always take your dose exactly as prescribed by your physician, and seek emergency medical help if you notice any of the above symptoms, or if you feel the urge to take more of your medication.

Contraindications for fluoxetine and tianeptine

Both fluoxetine and tianeptine, like many other antidepressant medications, can sometimes exacerbate symptoms of depression in certain individuals. If you feel your depression worsening or notice an increase in suicidal thoughts, ideation, or behaviors while taking either medication, it is crucial to seek immediate medical attention.

Neither fluoxetine nor tianeptine should be used if you are currently taking or have recently taken monoamine oxidase inhibitors (MAOIs). Always inform your physician about all the medications you are taking, as well as vitamins and herbal/dietary supplements. MAOIs in particular require a washout period of approximately 5 weeks before starting treatment with fluoxetine to prevent dangerous interactions. Fluoxetine should not be taken alongside the antipsychotic medications pimozide or thioridazine.

How much do fluoxetine and tianeptine cost?

For the brand name versions of these drugs:

  • The price of 30 capsules of Prozac (fluoxetine; 20 mg) averages about $570, which works out to approximately $19/day.
  • Tianeptine is not prescribed in the US, so there are no brand-name medications and thus no pricing information available. In parts of Europe and Asia, brand-name tianeptine ranges in price, but generally costs under $2/day.

For generic versions:

  • Fluoxetine is available in packs ranging from 15 up to 1000 capsules (20 mg), with costs starting as low as $0.05/day if purchased in larger quantities. For patients taking higher doses, costs will generally not exceed about $1.00/day.
  • Tianeptine is primarily available as brand-name formulations in the countries in which it is authorized for use.

Remember that cost should never be the primary factor in your journey to find the medication that works best for your individual health profile.

Popularity of tluoxetine and tianeptine

Fluoxetine, including brand versions such as Prozac, was prescribed to approximately 22 million people in the USA in 2021, being one of the top 4 most-prescribed antidepressants. The prevalence of fluoxetine has been approximately steady over the last decade, maintaining its status as a cornerstone treatment for depression and anxiety disorders.

Tianeptine is an atypical antidepressant that is not approved by the FDA in the United States, but is approved for use in various countries in Europe and Asia. It operates through a unique mechanism compared to traditional SSRIs like fluoxetine, modulating glutamate receptors and influencing neuroplasticity, in addition to effects at mu-opioid receptors. While it has shown efficacy in treating major depressive disorder and has fewer of the characteristic side effects of SSRIs, such as sexual dynsfunction and weight gain, tianeptine's usage remains limited due to concerns about abuse potential at higher doses. It may also lead to dependency and subsequent withdrawal upon discontinuation. Consequently, tianeptine accounts for significantly fewer prescriptions worldwide compared to more established medications like fluoxetine. It is currently being studied in clinical trials for treatment-resistant depression (TRD) in the US.


Fluoxetine and tianeptine belong to entirely different classes of drugs, but both can be used to treat depressive and anxiety disorders. Fluoxetine is commonly known by the brand name Prozac, and is an established first-line therapy for major depression. Tianeptine has a unique mechanism as a modulator of the glutamate system, and also has opioid activity. It is not available in the US, but has shown promise as an effective and fast-acting alternative to SSRI antidepressants in outher countries. The comparison is thus not directly relevant for US patients, as tianeptine is currently not prescribed for depression (or anything else).

Fluoxetine has a side effect profile similar to that of many other SSRI antidepressants, while tianeptine presents a different side effect profile. Fluoxetine may be more likely to lead to sexual dysfunction and weight gain, but tianeptine carries a risk of abuse and commonly causes dry mouth, insomnia and nightmares, headaches, and constipation. However, both medications are generally well-tolerated when taken as prescribed and are effective in treating depression. Tianeptine and fluoxetine should only be taken under prescription by a healthcare professional. Patients should closely monitor their symptoms when starting either medication and seek medical help immediately if symptoms of depression worsen or if suicidial ideation and tendencies increase, or if any sudden health changes are noted.