Disgraced Crypto King Sam Bankman And The Selegiline Patch 

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) 
  • Meats: fermented or dry sausages (pepperoni, salami), aged, cured, unrefrigerated, pickled, smoked meats 
  • Caviar, dried, pickled, or smoked fish 
  • Overripe avocados, fava beans, sauerkraut, fermented soya bean, and soya bean paste 
  • Overripe fruits: canned figs, banana peel, orange pulp 
  • Beverages: chianti, sherry, liquors, all tap beers, unfiltered beer containing yeast 
  • Soy products: soy sauce, tofu 
  • Other: miso soup, yeast vitamin supplements, packaged soups 

Foods That are Allowed

  • 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. 

When Serotonin Goes Bad

Many medications that work as so-called antidepressants will increase serotonin by blocking the reuptake pump. In general, we think of increased serotonin in a patient with depression as a good thing, but what happens when increased serotonin goes bad? 

That is what we are here to talk about today, what happen when there is too much serotonin in the central nervous system?

Being prescribed too many serotonergic medications can result in Serotonin Syndrome which can range from mild to severe and is potentially fatal. It can present with muscle rigidity, hyperthermia, and altered mental status. 

When someone has increased muscle tone, and elevated temperature with no other explanation, it’s time to look at their medication list. Medications can increase serotonin release, block reuptake, or directly activate serotonin receptors. Common examples include linezolid, Fentanyl, and dextromethorphan.

Watching from drug interactions like CYP 450 inhibitors can increase medication levels resulting in serotonin syndrome. Whenever a new medication is prescribed consider doing a drug interaction check to make sure the new medication doesn’t inhibit a critical cytochrome. 

Mild forms of serotonin syndrome may cause diarrhea or tremor where the more severe cases are more likely to result from a drug overdose. 

Key Features of Serotonin Syndrome: 

  • Patient is on one or more serotonergic drugs 
  • The onset of symptoms is abrupt usually within 24 hours and symptoms peak rapidly 
  • There is increased tone in the legs more than the arms, tremor and hyperreflexia are present 
  • Vital signs show hypertension, hyperthermia, tachycardia, and tachypnea 
  • Labs can show increased creatinine kinase 

What is Clonus: 

  • Involuntary, rhythmic muscle contractions. 
  • It occurs more in the lower extremities 
  • To induce clonus, you flex the patient’s foot upward until there is rhythmic beating of the foot and ankle. If the beating continues beyond a couple of beats, it’s abnormal 

Treatment: 

  • For mild cases discontinue serotonergic medications and check for drug interactions. Use external cooling measures and start benzodiazepines. 
  • For moderate cases where the vital signs are worse and there is spontaneous clonus or agitation: use the same measures as above, increase the frequency and dose of the benzodiazepine, and start cyproheptadine 12 mg followed by 2 mg every 2 hours until improvement is seen followed by 8 mg every 6 hours for maintenance. Cyproheptadine is an anticholinergic, antihistamine, and anti-serotonergic medication 
  • In severe cases, where delirium develops and there is a failure to respond to other measures, admission to the ICU and the use of paralytics with intubation and ventilation are required 

Everything You Need to Know About Trintellix (Vortioxetine)

Introduction:

Vortioxetine is sold under the brand name Trintellix, and Brintellix and it’s approved for use in major depressive disorder. The name was changed to Trintellix in the U.S. due to confusion with Brillinta an anti-platelet medication. It was studied in generalized anxiety disorder (GAD) at lower doses, but the quality of the evidence is poor and does not appear to improve symptoms or quality of life in patients with GAD. 

I want to make a quick point before going into the details about the medication. When I say the effect size is moderate and Vortioxetine does not perform better than other options for depression, I’m not saying in an individual case that it may not outperform other antidepressants that the person has tried in the past. It very well might for that individual. I’m talking about on average in large sample sizes, Vortioxetine does not outperform other medications according to the current literature. It’s also not a go to medication for treatment resistant depression, the literature does not support this either.

The one place Vortioxetine does seem to stand out is cognitive function. Multiple studies have shown this medication to improve cognitive dysfunction associated with depression. It also appears to improve cognitive function in geriatric depression but failed to show any benefit in neurocognitive disorders like Alzheimer’s disease. It was also looked at as a potential treatment for attention deficit hyperactivity disorder (ADHD) but failed to show an adequate benefit in trials. 

Mechanism of Action and Receptor Targets

This medication falls into a class known as serotonin modulators and stimulators. It is thought to work by several different mechanisms:

-Serotonin reuptake inhibitor

-5-HT1A agonist (may diminish sexual side effects) 

-5-HT1B partial agonist 

-5-HT1D, 5-HT3 (may enhance noradrenergic and cholinergic activity that improves cognition while reducing nausea), and 5-HT7 antagonist (pro-cognitive and antidepressant effects) 

The most robust action is on serotonin reuptake and 5-HT3 antagonism, while the other interactions are considered minor. 

Target Affinity Ki (nM)Action 
SERT1.6Inhibition 
NET113Inhibition 
5-HT1A 15Agonist 
5-HT1B33Partial agonist 
5-HT1D 54Antagonist 
5-HT2C180 
5-HT3A3.7Antagonist 
5-HT719Antagonist 

Metabolism

Vortioxetine is metabolized by CYP2D6, 3A4/5, 2C19, 2C9, 2A6, 2C8 and 2B6, the half-life is 66 hours and it’s dosed one time per day. Reduction is dosing may be needed for patients taking strong CYP2D6 inhibitors (e.g. bupropion).

Dosing:

-5-20 mg/day 

-Tablets come as 5 mg, 10 mg, and 20 mg 

-The initial dose for depression is 10 mg which can be increased as needed to a maximum dose of 20 mg daily. 

-For GAD does were kept lower 5-10 mg/day range 

-Can be taken with or without food 

-It can be stopped without a tapper 

Side Effect:

Common side effects include nausea, vomiting, constipation, sexual dysfunction, weight gain is unusual but possible. Nausea and sexual dysfunction were the most common side effects; all other side effects were reported in less than 10% of cases. 

Sexual dysfunction was found in both the plebe group and the treatment arm. The incidence was 14-20% for placebo and 16-34% for those in the treatment arm.

Rare life-threatening side effects include seizures, induction of mania and suicidal ideation. 

Avoid using tramadol as it can increase the risk of seizure, and do not combine with MAOIs as this can result in serotonin syndrome. 

It’s generally not recommended in pregnancy. 

Conclusion

While this medication may be helpful for some individuals there is no evidence to support its use in treatment resistant depression or other disorders outside of the primary indication major depressive disorder. There does seem to be a benefit for patients who have significant cognitive dysfunction as a result of depression and maybe that is where this medication best fits into a treatment plan. The main side effects are nausea and sexual dysfunction which are common with all antidepressant options. You must also consider the cost of the medication in comparison to duloxetine which outperformed Vortioxetine in some clinical trials.

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