A study in JAMA Psychiatry explores how functional MRI (fMRI) biomarkers can help distinguish major depressive disorder (MDD) 😔 from healthy individuals. Researchers found that regional homogeneity (ReHo) patterns in the brain are a more reliable marker for MDD than traditional structural MRI 🏗️.
🔬 Why does this matter? 👉 Better Diagnostics: fMRI could lead to more objective ways to diagnose depression, reducing reliance on self-reporting. 👉 Early Detection: One day, brain scans 🏥 might help identify people at risk before symptoms fully develop. 👉 Personalized Treatment: Understanding individual brain patterns could help guide targeted interventions like therapy or medication.
Could brain scans be the future of depression diagnosis? 🤔 Drop your thoughts below! ⬇️
A recent 8-week double-blind, randomized, placebo-controlled trial investigated whether oral creatine monohydrate (5g/day) could enhance the effects of cognitive-behavioral therapy (CBT) in treating major depressive disorder (MDD)—especially in under-resourced areas where access to treatment is limited.
🔬 Why Does This Matter? While CBT is a gold-standard therapy for depression, many patients do not achieve full remission. This study explored whether creatine—widely used for muscle and brain energy metabolism—could provide an extra boost to treatment.
🧠 Key Findings: ✅ Participants receiving creatine + CBT had greater reductions in depression symptoms (measured by the Hamilton Depression Rating Scale) compared to those receiving placebo + CBT ✅ Reported improvements in mood, energy levels, and cognitive function ✅ Creatine was well-tolerated, with no significant safety concerns ✅ CBT was delivered once weekly by trained therapists
⚠️ Study Limitations: 🔹 Small sample size—larger studies are needed to confirm these findings 🔹 Short trial duration—long-term effects are still unknown 🔹 Study population—results may not generalize to all individuals with MDD
💡 What’s Next? If larger studies confirm these results, creatine could become an accessible, affordable adjunct to therapy, particularly in communities with limited mental health resources.
What do you think? Could a common fitness supplement help improve mental health? Let’s discuss! ⬇️
Gepirone may have flown under the radar for many of us. I’ll admit, it didn’t generate much excitement on my end. However, it recently crossed a significant milestone: FDA approval as an antidepressant. But let’s not overlook its rocky path to getting there—a journey marked by hurdles and setbacks.
The road to FDA approval for gepirone was anything but smooth. Its initial development began decades ago, but the approval process faced repeated delays and rejections. Questions about efficacy and study designs kept it in limbo for years. What ultimately got it across the finish line was a re-analysis of data demonstrating robust effects in specific populations, particularly those with significant depressive symptoms. This serves as a reminder that persistence and rigorous data reassessment can change the trajectory for medications once thought to have limited potential.
Now that gepirone is finally available, the big question is: should we care? If so, where does it fit into our treatment algorithms for adult depression?
With a mechanism targeting the serotonin 1A receptor as a partial agonist, gepirone offers a unique profile compared to SSRIs, SNRIs, and other standard antidepressants. Its anxiolytic effects may make it particularly appealing for patients with co-occurring anxiety. However, like any medication, it isn’t without its downsides.
Potential side effects include nausea, dizziness, fatigue, and headache. These are generally mild, but it’s important to monitor for tolerability in sensitive patients. Gepirone also carries warnings about potential interactions with other serotonergic agents, raising the risk of serotonin syndrome. While this risk isn’t unique to gepirone, it’s a critical point to keep in mind when integrating it into a treatment plan.
So, where does gepirone fit? Will it serve as a first-line option for certain patients, or will it find a niche role for those with specific tolerability issues or suboptimal responses to other antidepressants?
I’d love to hear your thoughts. Is gepirone a tool worth adding to our arsenal, or just another option that might not shift the needle much in clinical practice?
Did you know that in depression, the brain’s wiring can actually amplify negative experiences? Recent research from the Institut Pasteur and collaborators explored this phenomenon, finding that depression alters specific neurons in the amygdala. These changes can reduce activity in neurons that process positive stimuli while overactivating those that process negative stimuli. This “negativity bias” means people with depression often perceive even neutral events through a negative lens.
In studies with mouse models of depression, activating neurons responsible for positive perceptions helped reduce depressive behaviors. This groundbreaking discovery could pave the way for new treatments aimed at rebalancing these circuits, especially for people who don’t respond to conventional therapies.
By understanding depression’s effects on the amygdala, researchers hope to develop more targeted and effective therapies for those resistant to current treatments. This is a step toward a more personalized approach to mental health.
Monoamine oxidase inhibitors (MAOIs) are a class of medications primarily used to treat depression. They work by inhibiting the activity of monoamine oxidase enzymes (MAO-A and MAO-B). These enzymes are responsible for breaking down neurotransmitters such as serotonin, norepinephrine, and dopamine in the brain. By inhibiting these enzymes, MAOIs increase the levels of these neurotransmitters, which can help improve mood and alleviate depressive symptoms.
Common Medications
Phenelzine (Nardil)
Tranylcypromine (Parnate)
Isocarboxazid (Marplan)
Selegiline (Emsam) – Available as a transdermal patch
Side Effects
MAOIs can have significant side effects and interactions, which is why they are often not the first choice for treating depression. Some common side effects include:
Hypertensive Crisis: Consuming foods high in tyramine (such as aged cheeses, cured meats, and fermented products) can cause dangerously high blood pressure.
Orthostatic Hypotension: A sudden drop in blood pressure when standing up, leading to dizziness or fainting.
Insomnia: Difficulty falling or staying asleep.
Weight Gain: An increase in body weight over time.
Sexual Dysfunction: Decreased libido, erectile dysfunction, or difficulty achieving orgasm.
Headaches: Frequent or severe headaches.
Edema: Swelling, particularly in the lower limbs.
Fatigue: General feeling of tiredness or lack of energy.
Dry Mouth: Reduced saliva production, leading to a dry sensation in the mouth.
Precautions
Dietary Restrictions: Due to the risk of hypertensive crisis, patients on MAOIs must follow strict dietary restrictions to avoid tyramine-rich foods.
Drug Interactions: MAOIs can interact with numerous medications, including over-the-counter drugs, other antidepressants, and certain pain medications, potentially leading to severe or life-threatening conditions.
Medical Monitoring: Regular monitoring by a healthcare professional is essential to manage and mitigate potential side effects and interactions.
MAOIs can be effective for certain patients, particularly those who have not responded to other antidepressant treatments. However, their use requires careful management due to their side effect profile and interaction potential.
The article on Clinical Outcomes of Continuation and Maintenance Electroconvulsive Therapy (ECT) highlights the role of ECT in preventing relapses in patients with major depressive disorder. Continuation (C-ECT) and maintenance (M-ECT) ECT, when used after an initial successful acute ECT response, are shown to be effective in reducing the recurrence of mood disorders, particularly when combined with pharmacotherapy. Despite its proven benefits, this therapeutic approach is underutilized. Studies also suggest that C-ECT and M-ECT are well-tolerated with no significant cognitive decline
Psychiatry’s fascination with ketamine continues, despite growing evidence that it may not be the miracle treatment some once hoped for. It’s clear that ketamine is not disease-modifying, meaning patients treated for depression with ketamine can still experience relapses. Even more concerning is that ketamine’s effects are short-lived, with the average time to relapse being just 2-4 weeks.
This brings us to recent studies on oral extended-release ketamine for treatment-resistant depression (TRD). In a proof-of-concept study, twice-weekly dosing of extended-release ketamine showed statistically significant and clinically meaningful improvements in depressive symptoms. The treatment was generally well-tolerated, with a side effect profile that included reduced dissociation and sedation, though there were increases in blood pressure. Having a tablet form of ketamine could make the treatment more accessible, but it also raises concerns about potential abuse and diversion.
In my view, this is another symptom management tool for patients with TRD. However, the challenge remains that patients will likely need to continue ketamine treatment long-term without a clear dosing regimen. Nonetheless, the results were promising enough to lead to a phase-3 trial using 180 mg doses twice daily.
In ECT, there’s a common saying that “nothing good happens after 1 minute.” However, recent data suggests that nothing good happens if a seizure lasts less than 20 seconds either. Patients whose seizures lasted 30 seconds or longer during their first ECT session were more than twice as likely to achieve remission by the end of treatment compared to those with seizures under 20 seconds. Seizure durations around one minute appeared to provide the best chances for remission.
When Someone does not experience remission from major depression, we need to ask ourselves why, and come up with new solutions. This discussion will focus on the treatment of these individuals by first explaining what symptoms predict poor response to treatment and what symptoms of major depression result in the most psychosocial dysfunction.
What Causes Functional Impairment in Major Depression
From the STAR*D study we know that only 50% of patients respond to the first antidepressant treatment and only 33% achieve remission. An important question is why, or more specifically what factors result in poor outcomes.
Contrary to popular belief the medications we use to treat depression work well for some neurovegetative symptoms. Symptoms such as sleep, and appetite improve but the most debilitating symptoms often remain. Consistently Anhedonia and concentration are rated by patients with depression as the most debilitating. These cognitive symptoms such as trouble concentrating, difficulty planning, and poor attention lead to dysfunction at home and work.
Cognitive Symptoms Impair Work Performance
We all need to work to live, and depression is a leading cause of disability and poor work performance worldwide. What we know is that subjective measures of cognitive dysfunction are a better predictor of workplace performance than total depression severity. Someone with more severe overall depression scores may perform better at work than someone with perceived cognitive dysfunction from depression. This is one possible reason for a lack of improvement as many treatments do not address cognitive symptoms.
Anhedonia makes everything Worse
Possibly the most debilitating symptom of depression is anhedonia. Anhedonia is defined as loss of interest in previously pleasurable activities. A strong predictor of poor antidepressant outcome is the loss of interest. Making anhedonia a primary target of treatment would be wise if we want to improve outcomes in depression.
We have additional evidence that indicates how important anhedonia is for psychosocial function. Functional improvement is strongly associated with improvement in anhedonia. The improvement in anhedonia had a larger effect on psychosocial function than overall symptomatic response.
Emotional Blunting Effects on Treatment Outcomes
While people do not want to be depressed, they also do not want to be emotionally dull. Unfortunately, we know that emotional blunting is reported in nearly half of all depressed patients on antidepressants. This appears to be common to all monoamine antidepressants with bupropion having the lowest reported risk. Emotional blunting cannot be totally accounted for as just a side effect of treatment, it’s also a symptom of depression. However, the point remains the same emotional blunting results in poorer quality of remission.
Doctors Are Too Medically Oriented
The world of psychiatry is very different from other medical specialties. Psychiatry is really art based in science and if you try to approach mental health treatment from a strictly scientific basis you will never help anyone. When patients and physicians are asked to rank the symptoms of depression, they believe are most important, the lists do not match up.
Patients focus on restoration of positive affect by ranking things such as meaning and purpose in life, enjoyment in life, satisfaction with oneself as the top three most important things to address in depression. Clearly what should stand out to you here is that medication is unlikely to improve any of these factors.
Doctors rank depressed mood, hopelessness, and anhedonia as their top three symptoms to address. These symptoms are far better addressed by medication than the ones listed by patients although you could argue that hopelessness and anhedonia are difficult to treat with medication.
The effect of Loneliness on Health Outcomes
I’ve talked about this before and it continues to be a major concern in our modern world. We are the most connected we have ever been as a society with the advent of social media and the internet, yet no one feels connected. This is an existential crisis for all of us and I haven’t heard many good solutions. Time and time again we go back to the same things such as the internet and social media to feel connected and they continue to let us down. Not only is this emotionally taxing, but it’s also effecting our physical health as well. Here is yet another example of something that is very important for depression treatment outcomes that medication cannot fix.
Conclusion
What does this all mean? Should we stop attempting to use medication for the symptoms of depression? For me these findings indicate we need to screen more carefully for these specific symptoms that result in poor outcomes. We need to improve our psychosocial treatments to help people address ways to enhancing meaning and purpose in their lives. We need to recognize the limitations of medications. Medications have a place and do address some of the symptoms associated with depression, they just aren’t the ones patients believe are most important in their lives.
There has been a lot of news recently about Sam Bankman, the onetime billionaire turned supervillain. At its peak, his company FTX had an in-house performance coach and psychiatrist named George K. Lerner. It’s unclear how many FTX employees Dr. Lerner treated but he did admit to treating some for ADHD and stated “the rate of ADHD at FTX was in line with most tech companies” whatever that means. I’m not here to debate the practices of the good doctor, but Bankman was known to talk publicly about experimenting with focus-enhancing medications. The main medications he allegedly used to become limitless were stimulants such as Adderall and the more interesting one to me and the topic of this week’s video the selegiline patch.
We are going to discuss selegiline in depth and try to understand why a medication primarily used to treat Parkinson’s may be useful for enhancing focus, creativity, and productivity in the fast-paced world of cryptocurrency.
What is Selegiline?
Although many may not have heard of this medication, it’s actually a very old concept in psychiatry. A common “pimping” question in psychiatry residency is what was the first antidepressant medication? Most residents will say it was the tricyclic antidepressants which isn’t a bad guess but it’s not correct. The correct answer is the monoamine oxidase inhibitors (MAOIs) specifically iproniazid a failed treatment for tuberculosis. In 1952 researcher noted that patients receiving this medication became unusually happy, this was shocking considering the medication did nothing for their tuberculosis.
Transdermal selegiline is a tissue selective MAOI (MAO-A and MAO-B inhibitor in the brain) and a relatively selective MAO-B inhibitor in the gut. This is an important point, and I will explain more about it as we move through this topic.
How Do MAOIs Work?
We are speaking about the transdermal selegiline patch here but there is also an oral version that is not approved for major depressive disorder and is a selective MAO-B inhibitor.
The transdermal patch acts in the brain as an irreversible inhibitor of both MAO-A and MAO-B which are enzymes responsible for breaking down norepinephrine, serotonin, and dopamine which in turn will boost the noradrenergic, serotonergic, and dopaminergic neurotransmission.
In lay terms this medication increases the availability of all three major neurotransmitters so that more serotonin, norepinephrine, and dopamine is available to act on post synaptic receptors affecting changes in cells and circuits involved in depression.
FDA Approvals for Selegiline
This is a little complicated because news outlets have stated the medication is only used for Parkinson’s disease which is true if we are talking about the oral tablets. The transdermal patch is FDA approved for major depressive disorder.
Off label use includes the treatment of treatment resistant depression, panic disorder, social anxiety (which MAOIs are usually superior at treating), treatment resistant anxiety, and Alzheimer’s disease.
How to Dose Selegiline
The transdermal patch comes in various doses:
6 mg/24 hours
9 mg/24 hours
12 mg/24 hours
The initial dose for depression is 6 mg/24 hours and it can be increased by 3 mg/24 hours every 2 weeks to a maximum dose of 12 mg/24 hours. Dietary modification to restrict tyramine from food sources is not required for the 6 mg/24hr patch but at higher doses the same food restrictions are required as other oral MAOIs such as phenelzine. This will be important for our next discussion on side effects.
Side Effects of Selegiline
Before starting the medication, the patient should be aware of the potential for increased blood pressure.
Notable Side effects include
Skin reactions at the site of application (the location of the patch should be rotated daily)
Headaches
Dry mouth
Diarrhea
Insomnia
Sedation
Possible weight gain
Serious side effects include:
Hypertensive Crisis
Seizure
Induction of manic episodes in bipolar disorder
Contraindications when combined with:
Meperidine
Another MAOI
SSRIs, SNRIs, TCAs, tramadol
Dextromethorphan
St. John’s wort
Methadone
History of Pheochromocytoma
Elective surgery
Proven allergy to selegiline
The Dreaded Tyramine Reaction
I believe that MAOIs might be the most effective of the antidepressants because of their ability to affect all three major neurotransmitter circuits, but they are rarely used clinically. In most residency training programs, we are not taught to use these medications. The main barrier is the dietary restrictions and risk for hypertensive crisis if the diet is not followed.
This diet should be started a week or so before staring the medication. It allows the patient time to get accustomed to the dietary recommendations before being on the medication when the stakes are higher. The diet must be followed for 2 weeks after stopping the MAOI as it can take time for the MAO enzymes to regenerate due to irreversible inhibition.
Tyramine is an amino acid that is found in some foods, and it helps to regulate blood pressure. MAOIs are responsible for breaking this amino acid down so it’s inactive and unable to causes an increase in blood pressure. When you block MAO excess tyramine will be available to affect blood pressure.
Ingestion of a high tyramine meal is generally considered to be any meal with 40 mg or more in the fasted state. For the low dose transdermal patch 6 mg/24 hours studies show that 200-400 mg of tyramine in the fasted state is required for a hypertensive response. In general, at low doses dietary modification is not required. If the dose is increased to 12 mg/24 hours than 70-100 mg of tyramine is required for a hypertensive response. Although dietary modification may not be required at higher doses, it’s safer to avoid tyramine rich foods once the selegiline dose is increased and to be cautious at lower doses as well.
Low Tyramine Diet Principles
When a patient is on an MAOI diet they should only eat things that are fresh. This goes for food that are stored as well as the storage process may affect the tyramine content. The patient should avoid foods that are beyond their expiration date and avoid fruits and vegetables that are overly ripe. Some cheeses are allowed in the diet, but all aged cheese should be avoided. The same can be said for meat products, fresh meats are fine, but aged or spoiled meats should be avoided.
Fermented products need to be avoided when MAOIs are being used. This goes for all fermented products without exception.
Chinese food and some other eastern foods should be avoided because they contain soy, shrimp paste, tofu, and soy sauces all of which are high in tyramine.
Fava and other broad beans should be avoided this includes Italian green beans.
Foods to Avoid
Matured or aged cheeses (cheddar, and blue examples)
Cheeses: cream cheese, ricotta, fresh cottage cheese, mozzarella, processed cheese slices like American cheese
Milk Products: yogurt, sour cream, and ice cream
Meat: fresh packaged or processed meat e.g. hot dogs
Beverages: coffee, tea, soda, up to a maximum of 2 drinks either 12 oz of canned or bottled beer or 4 oz of red/white wine.
Soy products: soy milk
Other foods: chocolate in moderation and monosodium glutamate in moderation
Onset of Action
The therapeutic effect is usually not immediate and still requires 2-4 weeks or longer once an adequate dose is reached.
Augmentation
For expert psychopharmacologist Only:
You may consider a stimulant such as d-amphetamine, or methylphenidate while watching for increased blood pressure, suicidal ideation, and activation of bipolar disorder)
Lithium
Seconded generation dopamine blocking medication
Mood stabilizing anticonvulsant
Advantages to using MAOIs
May be effective in treatment resistant depression
May improve atypical depressive symptoms such as hypersomnia and hyperphagia
Lower risk for weight gain and sexual side effects
Why Would Selegiline Improve Cognitive function?
Selegiline will increase dopamine and more dopamine in the prefrontal cortex theoretically will enhance cognitive function. A lot of the research on MAOIs and cognitive enhancement come from studies in neurodegenerative disorders such as Alzheimer’s disease. While promising as reported in several articles it does not appear that proper randomized controlled trials were ever conducted. If you watch my videos than you should know the risk of assuming that something that should theoretically work will also work clinically. This is the story of many medications in psychiatry. We also cannot extrapolate that to healthy individuals who do not have neurodegenerative disorders.
Selegiline is metabolized to l-amphetamine, and l-methamphetamine which are well known stimulants that may improve symptoms of attention deficit hyperactivity disorder (ADHD). Again, this is theoretical and has never been proven but based on the metabolism of the medication it makes sense that it may enhance cognition in those with ADHD or even healthy individuals.
People often forget that depression itself is a major reason for cognitive problems. Depression in elderly patients is sometimes referred to as pseudodementia because it can look like the individuals has substantial cognitive deficits in severe cases. It’s possible that the improvement in depressive symptoms is responsible for the enhanced cognitive function.
Conclusion
I think this is a good discussion because it highlights an often-forgotten class of medication in modern psychiatry that can be utilized for patients who have failed other medication options. Many psychiatrists are untrained or too scared to use these medications clinically. As far as cognitive enhancement and finding that limitless pill, I do not think this is it. While it may theoretically improve cognitive function it’s never been proven in randomized controlled trials. I would say the evidence supporting this idea is weak and may even be dangerous given the risk for hypertensive crisis.
