Stage 1: more than one adequate trial of 1 major class of antidepressants
Stage 2: Failure of more than 2 adequate trials of two different classes of antidepressants
Stage 3: stage 2 + TCA
Stage 4: Stage 3 + MAOI
Stage 5: Stage 4 + bilateral ECT
With every medication or neuromodulation procedure used that doesn’t work, the more treatment resistant the depression becomes.
Antidepressant Response Rates
Frist Medication Trial: 50% respond and 37% have remission
Second Medication Trial: Another 29% respond and 31% have remission
Third Medication Trial: 17% respond and 14% have remission
Fourth Medication Trial: 16% respond and 13% have remission
The overall cumulative remission rates are 67%, keeping in mind that people who progressed through more treatment stages had higher relapse rates and more residual symptoms including anhedonia, emotional blunting, and lack of motivation.
If someone is having a poor response to medication, what do you do?
We know that bipolar disorder is missed in a significant number of patients who present with depression about one in five will be misdiagnosed. We also know that antidepressants can be mood destabilizing in bipolar illness resulting in mixed features and rapid cycling. Other things that can interfere with response include substance use disorder, personality traits, and PTSD.
Medical Comorbidities that can interfere with antidepressant response include hypothyroidism, Cushing disease, Parkinson’s disease, cancer, vitamin/nutritional deficiencies, and viral infections
Psychosocial factors that contribute to treatment resistance
-Female sex
-Older Age
-Single Unmarried (happiness studies indicate that good relationships are very important)
-Unemployment
Symptoms that make TRD more Likely
-Recurrent episodes usually 3 or more
-Severe depression and inpatient admission
-Anxiety, Insomnia, or Migraine
When Your First Choice Fails
There are several approaches
-Switch antidepressant classes
-Combine antidepressants
-Add a dopamine blocking medication
-Add L-methylfolate
-Add Psychotherapy
-Start Neuromodulation
What’s the most effective strategy
Hands down the most effective thing to do if a patient has a poor response to the initial antidepressant treatment is to add a dopamine blocking medication. Response and remission rates are much higher, but it comes at the price of increased side effect potential.
What are the most used Dopamine Blockers in Antidepressant Augmentation
-Quetiapine
-Olanzapine
-Risperidone
-Aripiprazole
-Ziprasidone
Older patients 65 years and older respond better to aripiprazole augmentation than switch to bupropion, or combination with bupropion.
Brexpiprazole: 1-3 mg/day Adjunctive for Depression
Most Common Concerns patients have about being on dopamine Blocking Medication
-Weight gain 60% of people report this concern
-Metabolic side effects
-EPS
-Sedation
-Akathisia
-Prolactin-related Effects
Anti-Inflammatory Medications
For those with elevated inflammatory biomarkers specifically c-reactive protein there is some emerging evidence that these treatments work.
-Medications like Celecoxib, Omega-3 fatty acids, statin drugs and minocycline
-Weight loss
-Effect Size: 0.55
-Higher response and remission rates
-May only work in those with high inflammatory biomarkers
Glutamate Modulators
-Ketamine Infusions and Esketamine: both work and a reasonable option if TRD
-There are several medications in development
Psychotherapy in TRD
Unfortunately, what we find with TRD is psychotherapy does not prevent TRD, it doesn’t mean there is no benefit it just means future episodes will not be prevented by psychotherapy. On its own, psychotherapy may not be as helpful as we would like in TRD but when combined with medication it does help. That tells us about the importance of evaluating severity of depressive episode.
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.
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
