How Antidepressants Work
In this episode of the Stuff You Should Know podcast, Josh Clark and guest Gary Gulman explore how antidepressants work and their role in treating depression. They provide an overview of major depressive disorder and the biological model linking depression to neurotransmitter imbalances, which paved the way for developing antidepressants like selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other drug classes.
The episode also examines emerging alternative treatments like ketamine and psilocybin, as well as factors that can influence antidepressant response, such as genetic variations, drug interactions, and brain development in younger patients. Offering insights into the complexities of depression and its management, this episode serves as a guide to understanding the various pharmacological approaches to this prevalent condition.
This is a preview of the Shortform summary of the Mar 13, 2025 episode of the Stuff You Should Know
Sign up for Shortform to access the whole episode summary along with additional materials like counterarguments and context.
1-Page Summary
Overview of Depression and Antidepressant Treatment
Depression's Prevalence and Chronic Nature
Depression affects millions worldwide, with major depressive disorder ([restricted term]) afflicting an estimated 20 million American adults. Josh Clark notes that once a person suffers an episode of [restricted term], they have a 50-85% chance of experiencing another episode, making it a likely chronic or recurring condition.
Biological Model and Antidepressant Development
The prevailing biological model since the 1970s links depression to an imbalance of neurotransmitters, notably serotonin. This led to the development of antidepressants designed to modulate neurotransmitter levels and transmission in the brain, although their exact mechanisms are still not fully understood.
Treatment Approaches
Treatment for depression now incorporates lifestyle changes, exercise, therapy, and pharmaceuticals. Gary Gulman shares how simple activities like walking helped during his depressive episodes.
Classes of Antidepressants
SSRIs: Common First-Line Treatment
Selective Serotonin Reuptake Inhibitors (SSRIs) like [restricted term] increase serotonin availability by blocking its reuptake. With relatively fewer side effects, SSRIs are often the preferred initial treatment.
Tricyclics: More Side Effects, Reserved for Treatment-Resistant Cases
Tricyclic antidepressants inhibit reuptake of serotonin and [restricted term] but have higher risks of side effects and overdose, so they are typically only used for treatment-resistant depression.
SNRIs: Similar to SSRIs with Added [restricted term] Targeting
Serotonin and [restricted term] Reuptake Inhibitors (SNRIs) like [restricted term] mirror the actions of SSRIs while also targeting [restricted term] reuptake, offering potential added benefits.
MAOIs: Unique But Challenging Mechanisms
Monoamine Oxidase Inhibitors (MAOIs) prevent breakdown of monoamine neurotransmitters but require strict dietary restrictions due to interactions, making them less favored today.
Newer Alternative Treatments
[restricted term] Provides Rapid Relief
[restricted term], a dissociative anesthetic that modulates glutamate, is emerging as a promising fast-acting treatment for treatment-resistant depression.
Psilocybin Shows Lasting Effects
Studies on psilocybin indicate it may produce lasting improvements in depression, potentially outperforming SSRIs, by enhancing neuroplasticity.
Factors Impacting Antidepressant Response
Genetic Factors
Clark discusses how genetic variations, like in the serotonin transporter gene, can influence antidepressant response and side effects, highlighting the value of personalized treatment strategies.
Drug Interactions
Interactions between antidepressants, other medications, and foods can affect drug efficacy and safety, especially in cases of polypharmacy.
Brain Development
For patients under 25, whose brains are still developing, balancing the benefits and risks of altering brain chemistry with antidepressants is crucial.
1-Page Summary
Additional Materials
Clarifications
- The biological model linking depression to an imbalance of neurotransmitters suggests that disruptions in the levels or functioning of certain brain chemicals, like serotonin, may contribute to the development of depressive symptoms. This theory has guided the development of antidepressant medications that aim to correct these imbalances by targeting specific neurotransmitters in the brain. However, it's important to note that while this model is widely accepted, the exact mechanisms underlying depression and the role of neurotransmitters are still not fully understood.
- The exact mechanisms of how antidepressants work in the brain are not fully understood. While it is known that they modulate neurotransmitter levels, the precise ways in which they alleviate symptoms of depression remain complex and not completely elucidated. Researchers continue to study and explore the intricate interactions between antidepressants and the brain's neurotransmitter systems to gain a deeper understanding of their mechanisms of action. This ongoing research aims to uncover more insights into how antidepressants exert their therapeutic effects on individuals with depression.
- Tricyclic antidepressants are an older class of medications used to treat depression. They are effective but have a higher risk of side effects compared to newer antidepressants like SSRIs. Additionally, tricyclic antidepressants can be more dangerous in cases of overdose compared to other types of antidepressants. These medications require careful monitoring and dosing due to their potential for serious side effects and toxicity.
- Monoamine Oxidase Inhibitors (MAOIs) are a class of antidepressants that work by blocking the enzyme monoamine oxidase, which breaks down neurotransmitters like serotonin, dopamine, and [restricted term]. MAOIs have unique mechanisms compared to other antidepressants, and they are typically used as a last resort due to their potential side effects and interactions with certain foods and medications. Dietary restrictions are necessary when taking MAOIs to avoid a dangerous increase in blood pressure, known as a hypertensive crisis, which can occur when consuming foods high in tyramine, such as aged cheeses, cured meats, and some alcoholic beverages. These dietary restrictions are crucial to prevent serious health risks and ensure the safe and effective use of MAOIs in treating depression.
- [restricted term] is a dissociative anesthetic that has shown promise in rapidly alleviating symptoms of treatment-resistant depression. It works differently from traditional antidepressants by modulating the glutamate system in the brain. [restricted term] is often administered in a controlled medical setting due to its potential for misuse and side effects. Its fast-acting nature makes it a valuable option for individuals who have not responded well to other forms of depression treatment.
- Psilocybin, a compound found in certain types of mushrooms, has shown promise in studies for its potential to produce lasting improvements in depression. It is believed to work by enhancing neuroplasticity, which is the brain's ability to reorganize itself and form new connections. This mechanism may contribute to its effects on mood and mental health. Psilocybin is being researched as a potential alternative treatment for depression, with some studies suggesting it could be more effective than traditional antidepressants like SSRIs.
- Genetic variations can impact how individuals respond to antidepressant medications and the likelihood of experiencing side effects. Specific genes, like the serotonin transporter gene, play a role in determining an individual's reaction to antidepressants. Understanding these genetic differences can help tailor treatment plans for better outcomes. Personalized medicine considers genetic factors to optimize antidepressant therapy.
- Interactions between antidepressants, other medications, and foods can impact how the antidepressants work in the body and their safety. Certain medications or foods can alter the effectiveness of antidepressants or increase the risk of side effects. It's important to consult with a healthcare provider to understand potential interactions and make informed decisions about medication use. Maintaining open communication with healthcare professionals can help manage any risks associated with these interactions.
Counterarguments
- The biological model of depression being solely or primarily due to neurotransmitter imbalances is overly simplistic and may not capture the full complexity of the condition, which can also involve genetic, environmental, and psychological factors.
- The efficacy of antidepressants, particularly SSRIs, has been debated, with some studies suggesting that their benefits may be more modest than initially thought, especially for mild to moderate depression.
- The long-term effects of antidepressants on brain chemistry and overall health are not fully understood, and there is concern about issues related to dependency and withdrawal symptoms.
- Lifestyle changes and therapy may be as effective as medication for some individuals, and emphasizing pharmaceutical treatments might overshadow the importance of these non-pharmacological interventions.
- The role of exercise, such as walking, in treating depression is supported by research, but its effectiveness can vary greatly among individuals and may not be a sufficient standalone treatment for severe depression.
- The use of [restricted term] and psilocybin for depression is still relatively new, and while early results are promising, more research is needed to fully understand their long-term safety, efficacy, and potential for abuse.
- Genetic factors influencing antidepressant response are complex and not yet fully understood, and personalized treatment strategies based on genetics are still in their infancy.
- The potential risks and benefits of antidepressant use in individuals under 25 need careful consideration, but it's also important to recognize that untreated depression itself can have serious consequences on brain development and overall health.
Related Shortform Content
Get access to the context and additional materials
Overview of Depression and Treatment With Antidepressants
Depression is a prevalent mental health issue affecting millions worldwide, leading to a search for effective treatments, including the use of antidepressants.
Depression Affects Millions, With Sadness, Sleep Disruption, and Loss of Pleasure
Depression: Chronic or Recurring, Impairing Daily Life
An estimated 60 million adults in America are diagnosed with some form of depression, with 20 million of those having major depressive disorder ([restricted term]). [restricted term] is characterized by a persistent state of depression as opposed to bipolar disorder, which includes both mania and depression. The World Health Organization predicts that by 2030, depression will be the leading disease globally, revealing its chronic or recurrent nature.
Historically known as melancholy, depression has been interpreted and treated variously across cultures, sometimes with positive rewards and other times with punitive or harmful practices. Josh Clark points out that once a person suffers an episode of [restricted term], they are 50 to 85 percent likely to experience another, making it likely to be a chronic or recurring issue in one's life.
Biological Model Links Neurotransmitter Imbalance, Notably Serotonin, to Depression, Prompting Antidepressant Development
Antidepressants Modulate Neurotransmitter Levels and Transmission In the Brain
The biological model of depression suggests that it is caused by an imbalance of neurotransmitters, particularly serotonin. This has been the prevailing theory since the 1970s, leading to the development of antidepressants. Antidepressants are designed to modulate neurotransmitter levels and transmission in the brain. The University of Colorado posits that antidepressants alleviate symptoms not by rebalancing neurotransmitter levels but by aiding brain circuits stuck in a depressed state to recover, thus improving neuroplasticity.
However, studies challenging the biological model have shown that people with [restricted term] don't always have lower serotonin levels compared to others, implying that the exact mechanism by which antidepressants treat depression is still not fully understood. Despite ...
Here’s what you’ll find in our full summary
Overview of Depression and Treatment With Antidepressants
Additional Materials
Clarifications
- The statistics mentioned in the text about the number of adults in America diagnosed with depression and major depressive disorder ([restricted term]) are estimates provided for illustrative purposes and are not precise figures. The text highlights that an estimated 60 million adults in America are diagnosed with some form of depression, with 20 million of those having major depressive disorder ([restricted term]). These numbers serve to emphasize the significant impact of depression on the population and are used to underscore the prevalence of these mental health conditions in society.
- Depression, historically referred to as melancholy, has been recognized and treated differently across cultures throughout history. Various societies have viewed depression through different lenses, sometimes offering supportive and beneficial treatments, while in other cases, harmful or punitive practices were employed. Understanding the historical context of depression sheds light on the diverse ways in which this mental health condition has been perceived and managed over time.
- The biological model of depression suggests that an imbalance in neurotransmitters, such as serotonin, may contribute to the development of depressive symptoms. Antidepressants are medications designed to target these neurotransmitter imbalances in the brain. While the exact mechanism by which antidepressants alleviate depression is not fully understood, they are believed to help regulate neurotransmitter levels and improve brain circuit function. Studies have shown that antidepressants can be more effective than a placebo in treating depression, despite ongoing debates about the precise role of serotonin in depression.
- Antidepressants are believed to help improve neuroplasticity by aiding brain circuits that are stuck in a depressed state to recover. Neuroplasticity is the brain's ability to reorganize itself by forming new neural connections throughout life. By modulating neurotransmitter levels and transmission, antidepressants may facilitate this process, potentially leading to improvements in mood and overall mental health.
- The biological model of depression suggests that imbalances in neurotransmitters, like serotonin, contribute to the condition. However, studies have shown that not all individuals with major depressive disorder ([restricted term]) have lower serotonin levels, which challenges the simplistic serotonin imbalance theory. This discrepancy indicates that the exact mechanisms through which antidepressants alleviate depression symptoms are not fully understood, highlighting the complexity of depression and the need for further research in this area.
- In the past, enemas and baths were used as treatments for various health conditions, including mental health issues like ...
Counterarguments
- The biological model of depression is overly simplistic and may not capture the complexity of the condition, which can also be influenced by genetic, environmental, and psychological factors.
- The effectiveness of antidepressants can vary greatly among individuals, and some may experience little to no benefit, or even adverse effects.
- The reliance on pharmaceuticals for treating depression may overshadow the importance of addressing underlying social, economic, and personal issues that contribute to the condition.
- The prediction that depression will be the leading disease globally by 2030 may not account for potential advancements in prevention and treatment strategies that could alter this trajectory.
- The emphasis on neurotransmitter imbalance may lead to an underappreciation of non-pharmacological interventions, such as psychotherapy, which can be effective in treating depression.
- The increase in diagnoses and prescriptions of antidepressants could reflect not only a growing acknowledgment of depression but also an over-medicalization of normal emotional states and societal pressures to conform to a standard of mental well-being.
- The narrative that once a person experiences [restricted term], they are likely to have ano ...
Related Shortform Content
Get access to the context and additional materials
Different Classes of Antidepressants (SSRIs, Tricyclics, SNRIs, MAOIs)
The hosts delve into the various classes of antidepressants, highlighting their mechanisms and varying impacts.
SSRIs: Commonly Prescribed Antidepressants Increasing Serotonin Availability
Selective Serotonin Reuptake Inhibitors (SSRIs) came on the scene in the mid-1980s, with [restricted term] ([restricted term]) being the first one available in 1988. This class, which includes other drugs such as [restricted term] ([restricted term]), [restricted term] ([restricted term]), and [restricted term] ([restricted term]), focuses specifically on blocking the reuptake of serotonin back into the presynaptic cell, leaving more serotonin available in the synaptic cleft. SSRIs are known for their once-a-day dosing, as seen with [restricted term] due to its long half-life, helping patients adhere to their treatment.
SSRIs' Fewer Side Effects Make Them Preferred First-Line Treatment
Despite possible side effects like anxiety, sexual dysfunction, and vertigo, SSRIs have the fewest compared to other classes, making them a preferred first-line treatment. Doctors may start patients on a low dose and increase it slowly. If one SSRI doesn't work, another within the class can be tried, and due to their general efficacy and lower side effect risk, SSRIs are often used at the onset of depression treatment.
Tricyclics Inhibit Serotonin and [restricted term] Reuptake, but Have Higher Side Effect Risks
Tricyclic antidepressants are reuptake inhibitors not only for serotonin but for other neurotransmitters as well, which might lead to their significant side effects. This class includes drugs such as Noortriptyline and [restricted term].
Tricyclic Antidepressants: Usually Reserved For Treatment-Resistant Cases
Due to their riskier side effect profile and the potential for overdose, tricyclics have been largely replaced by newer antidepressants. They may still be recommended for treatment-resistant cases or specific conditions like neuropathic pain. Additionally, their use carries a black box warning regarding an increased risk of suicide.
SNRIs Target Serotonin and [restricted term] Reuptake and Are an Alternative to SSRIs With Similar Efficacy and Side Effects
Appearing in the mid-'90s, Serotonin and [restricted term] Reuptake Inhibitors (SNRIs) such as [restricted term] ([restricted term]) and [restricted term] ([restricted term]) mimic the actions of SSRIs but with additional targeting of [restricted term]. They have similar side effects and efficacy to SSRIs, and ...
Here’s what you’ll find in our full summary
Different Classes of Antidepressants (SSRIs, Tricyclics, SNRIs, MAOIs)
Additional Materials
Counterarguments
- SSRIs, while having fewer side effects, still carry risks and may not be well-tolerated by all patients.
- The effectiveness of SSRIs can vary greatly among individuals, and some may not respond to them at all.
- Tricyclics, despite their side effects, can be very effective for certain patients and should not be discounted solely based on their risk profile.
- SNRIs may not be suitable for all patients, especially those with certain pre-existing conditions like hypertension.
- The dual targeting mechanism of SNRIs does not necessarily translate to clinical superiority over SSRIs for all patients.
- MAOIs, though ...
Actionables
- You can create a personal medication diary to track your experiences if you're prescribed SSRIs, SNRIs, or other antidepressants. Start by noting down the name of the medication, dosage, and any side effects you observe daily. This will help you and your healthcare provider understand your response to the medication and make informed decisions about your treatment plan.
- Develop a dietary checklist if you're prescribed MAOIs to ensure you avoid foods that could interact negatively with your medication. Include common foods that are high in tyramine, such as aged cheeses and cured meats, and check this list before meals. This proactive approach can prevent adverse effects and make managing your diet easier.
- Engage in a peer support group online or in you ...
Related Shortform Content
Get access to the context and additional materials
Newer Alternative Treatments For Depression (Ketamine, Psilocybin)
Chuck Bryant and Josh Clark discuss the emergence of [restricted term] and psilocybin as promising treatments for major depressive disorder ([restricted term]), particularly for those resistant to traditional therapies.
[restricted term], a Dissociative Anesthetic, Shows Promise For Treatment-Resistant Depression
Bryant mentions that [restricted term], a psychedelic treatment, is leading in official studies and government support compared to other alternative treatments like psilocybin.
[restricted term] Modulates Glutamate, Regulating Mood and Providing Rapid, Sustained Depression Relief
[restricted term] has been tested as a breakthrough treatment for depression, serving as a last resort for those who haven’t had success with traditional treatments. Due to its potential, the FDA expedited the approval process for [restricted term]. There is an FDA-approved prescription version of esketamine, derived from [restricted term], that modulates glutamate in the brain, which affects mood regulation and can provide rapid and sustained relief from depression.
Psilocybin's Potential in Depression Treatment, With Studies Showing Lasting Effects
Psilocybin's Neuroplastic and Mood-Enhancing Effects May Aid Treatment-Resistant Depression
No specific details are provided about studies on psilocybin's lasting effects in the given transcript chunk, but Chuck and Josh note that psilocybin produces promising results in depression treatment and differs from other treatments in that it may not require continual dosing.
A groundbreaking Johns Hopkins study in 2022 discovered that just two doses of psilocybin given two weeks apart had lasting effects for up to a year. Participants in the study saw their depression ratings begin at severely depressed and drop to just above the threshold for no depression a year after their psilocybin doses.
Another study from 2024 suggested that psilocybin could be at least as effective as SSRIs, if not more so, in treating [restricted term]. Psilocybin's potential to rewire the brain ma ...
Here’s what you’ll find in our full summary
Newer Alternative Treatments For Depression (Ketamine, Psilocybin)
Additional Materials
Counterarguments
- While [restricted term] and psilocybin show promise, their long-term safety profiles are not as well-established as traditional antidepressants.
- The rapid relief from depression symptoms provided by [restricted term] may lead to a reliance on its effects, potentially masking underlying issues without addressing them.
- The FDA's expedited approval process for esketamine may have been based on limited data, and further research is necessary to fully understand its efficacy and safety.
- Psilocybin's lasting effects are promising, but more extensive and diverse clinical trials are needed to confirm its efficacy across different populations.
- The comparison of psilocybin to SSRIs in terms of efficacy needs to be substantiated with larger, more comprehensive studies.
- The potential for psilocybin to rewire the brain is an exciting prospect, but the long-term implications of such changes are not yet fully understood.
- Using [restricted term] and psilocybin as last-resort treatments may inadvertently contribute to the stigma surrounding mental health by suggesting that these options are only for the most severe cases.
- The classification of [restri ...
Actionables
- You can start a personal journal to track your mood and any changes if you decide to pursue psychedelic therapy, noting down your emotional state, any side effects, and overall mental health progress. This can help you and your healthcare provider understand the effects of the treatment on your well-being and make informed decisions about continuing or adjusting the therapy.
- Consider joining or creating a peer support group for individuals exploring or undergoing psychedelic treatments for depression, where you can share experiences, discuss challenges, and provide mutual support. This can help reduce feelings of isolation and provide a sense of community during your treatment journey.
- Educate yourself on the legal status, potentia ...
Related Shortform Content
Get access to the context and additional materials
Factors Impacting Antidepressant Effectiveness (Genetics, Interactions, Age)
When it comes to treating depression, antidepressants can be a critical component of a patient's recovery plan. However, their effectiveness is influenced by various factors, including genetics, drug interactions, and the patient's age.
Genetic Factors, Like Serotonin Transporter Gene Variations, Can Affect Antidepressant Response, Worsening Symptoms for Some
Personalized Treatment and Genetic Testing Help Identify Appropriate Antidepressants
Josh Clark discusses that genetics play a significant role in how an individual responds to antidepressant medications. Specifically, a variation in the gene SLC 64A, known as the serotonin transporter gene, can make an individual feel worse after taking antidepressants. Antidepressants function by modulating serotonin levels in the brain, but this process can affect other bodily functions beyond mood regulation, such as sleep, digestion, and nausea. This complexity may contribute to the side effects experienced when taking these medications. As a result, personalized treatment strategies and genetic testing have become invaluable in identifying the most appropriate antidepressants for each person.
Interactions Between Antidepressants, Medications, and Foods Can Affect Drug Efficacy and Safety, Leading To Potential Adverse Effects
Monitoring and Managing Polypharmacy Is Crucial to Effective Antidepressant Treatment
Clark and Bryant discuss that antidepressants do not operate in isolation. Interactions between antidepressants, other medications, and even certain foods can significantly influence the efficacy and safety of the drug therapy. This is especially relevant in the context of polypharmacy, where patients take multiple medications simultaneously. Such drug interactions can lead to difficulty identifying which drugs are responsible for which effects and may lead to potential adverse reactions. He ...
Here’s what you’ll find in our full summary
Factors Impacting Antidepressant Effectiveness (Genetics, Interactions, Age)
Additional Materials
Clarifications
- The SLC6A4 gene, not SLC 64A, encodes the serotonin transporter protein that regulates serotonin levels in the brain. Variations in this gene can impact how individuals respond to antidepressants, potentially worsening symptoms for some. This gene variation can affect the effectiveness and tolerability of antidepressant medications, highlighting the importance of personalized treatment approaches and genetic testing in optimizing treatment outcomes.
- Polypharmacy is the term used when a patient is taking multiple medications simultaneously. In the context of antidepressant treatment, polypharmacy can lead to interactions between antidepressants, other medications, and even certain foods, affecting the efficacy and safety of the drug therapy. Managing polypharmacy is crucial to ensure that the effects of each medication are understood and potential adverse reactions are minimized. Monitoring and adjusting medication regimens can help optimize the effectiveness of antidepressant treatment in patients taking multiple medications.
- Antidepressant use in patients under 25 requires careful cons ...
Counterarguments
- While genetic factors like the serotonin transporter gene can influence antidepressant response, not all patients may have access to genetic testing, and the relationship between genetics and antidepressant efficacy is complex and not fully understood.
- Personalized treatment is ideal, but it may not be feasible in all healthcare settings due to cost, availability of genetic testing, and the need for specialized knowledge to interpret test results.
- Drug interactions are important to consider, but with proper management and communication between healthcare providers, many adverse effects can be mitigated, and not all interactions lead to serious consequences.
- Polypharmacy can be challenging, but for some patients with multiple health conditions, the benefits of taking multiple medications may outweigh the risks, and careful management can minimize potential problems.
- The concern for antidepressant use in individuals under 25 is valid, but it is a ...
Related Shortform Content
Get access to the context and additional materials
Create Summaries for anything on the web
Download the Shortform Chrome extension for your browser
