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.
In the first part of this series, we discussed anxiety and specifically generalized anxiety disorder (GAD) as a diagnosis. Now we are going to look at the research associated with the treatment of GAD and let the research inform our decision making about what works when a person presents with GAD. Some of these findings may surprise you.
SSRIs
Although the effect size of SSRIs in GAD is small, 0.33 they remain the recommended first line option for treatment. It’s also important to confirm that someone has had an adequate trial of SSRI treatment before assuming it’s not effective. The choice of which SSRI will depend on the side effect profile and other patient factors such as presence of insomnia, substance use, or pregnancy. Escitalopram is a good place to start, fluoxetine, or sertraline can be alternative options. Although paroxetine has the FDA approval for GAD it has more side effects like weight gain and sedation, along with several other factors that make this medication a poor first-line option. If the first medication trial is ineffective it’s reasonable to try a second SSRI or switch to the SNRI duloxetine.
When SSRIs Don’t Work
The next step in many cases is to try a medication from a different class. Two SNRIs have been well studied in GAD, venlafaxine, and duloxetine. Venlafaxine is not considered a first line choice due to the side effect profile and the small increase in efficacy. From the meta-analysis on anxiety treatments the effect size is 0.36 slightly better than the SSRIs but it would likely be undetectable clinically. Duloxetine is slightly better with respect to side effects and can be a good choice if you chose to use an SNRI for anxiety treatment. It has the added benefit of lower risk for sexual side effects compared to venlafaxine and possibly improved cognition.
Bupropion in Anxiety Disorders
There is some evidence for the use of bupropion in GAD. In one study small study of 25 participants bupropion beat the SSRI escitalopram head-to-head. Other lines of evidence include more improvement in GAD when bupropion was added as a combination treatment with SSRIs compared to adding buspirone. For clarification the effect size of buspirone in GAD is 0.17 which would be unlikely to produce any observable clinical improvement in anxiety symptoms. I largely stay away from buspirone unless it’s used to treat sexual side effects of SSRIs. Bupropion may be good option for patients who do not want the side effect profile of an SSRI. Although we lack the large RCTs for bupropion in GAD there is some evidence to support its use. The negative studies indicating bupropion worsened symptoms of anxiety come from studies in panic disorder where bupropion was found to worsen panic symptoms.
What About New Antidepressants?
Vortioxetine had a lot of hype when it first came out, and many believed it would work for GAD. Unfortunately, like many medications when we believe something should theoretically work based on the mechanism of action, we are sadly disappointed. This is one of those cases. The effect size was found to be 0.12 and it did not even cross into the small range. This medication performed worse than buspirone for GAD.
Vilazodone also had one positive study published for GAD. Again, based on the MOA it should work just fine, it has typical SSRI like effects in addition to 5-HT1A effects like buspirone, you should get the best of both worlds theoretically. This one positive study was followed by two distinctly negative studies and a calculated effect size of 0.26 which is considered small.
Both were not submitted for FDA approval for GAD based on the negative results.
The Hydroxyzine Argument
Hydroxyzine is an antihistamine that’s been out for a long time. As I stated earlier it has approval for tension associated with psychoneurosis which is the old psychanalytic way of describing anxiety. It’s often seen as ineffective, but the effect size was higher than SSRIs and SNRIs for the treatment of GAD. Hydroxyzine had an effect size of 0.45, and we may want to reconsider the use of this medication. Some limitations are the size of the studies and duration of the studies, but this still provides a fair amount of evidence that hydroxyzine may perform better than we think.
Quetiapine Surprised Me
Quetiapine is an antipsychotic medication usually not considered as a treatment option for anxiety disorders. However, the effect size was large with a range from 1.0 to 2.2. To put this in perspective this medication outperformed SSRIs, SNRIs, and benzodiazepines. Why did it not gain FDA approval? If you watched my other videos, you should know that the side effect profile is difficult to tolerate. Metabolic side effects and sedation are common, and the FDA does not view anxiety disorders as significant enough to warrant this degree of risk. One place where this medication may be very useful is in bipolar disorder with severe anxiety. We avoid antidepressants in this population at all costs, quetiapine offers a good option with strong evidence and strong antidepressant effects in bipolar depression.
Where this fits in clinical practice for me is as a 3rd or 4th line option after all other avenues have been explored except for bipolar disorder as stated above. The antipsychotic medications have been known to have a positive effect on anxiety, but the limitation remains side effects.
Anxiety as a less Severe Form of Psychiatric Illness
According to the FDA medications like aripiprazole and quetiapine are reasonable adjunctive therapies for patients with major depression that does not respond to first line treatment options. This is not their view for anxiety disorders that respond poorly to first line options. When we look at disability caused by depression and anxiety there isn’t much difference in the odds of being disabled for depression vs anxiety (3.5 Vs 3.1). For whatever reason we continue to view anxiety as less significant although DSM does not identify a clear diagnostic hierarchy.
Things like psychotherapy are often recommended as first line options. In the 1980’s when GAD was first conceived, it was thought to be a mild disorder where psychotherapy is the most effective treatment. In fact, psychotherapy did well it had an effect size of 0.5 which is nearly the same as benzodiazepines. Psychotherapy is a good place to start for anyone presenting with an anxiety disorder. I’m also a big believer of combining psychotherapy and medication for anxiety disorders.
What about Benzos?
Benzodiazepines can have all sorts of effects on the body. Largely we think of the benefits of benzodiazepines in anxiety disorders as having a major effect on the physical symptoms of anxiety and not so much on the chronic worry that characterizes the disorder. Many of the effects of benzodiazepines would not be measured by traditional anxiety rating scales based on the updated conception of GAD. Nevertheless, Benzodiazepines had an effect size of 0.4-0.5 which falls into the moderate range for GAD.
A final Option to Consider
Silexan the proprietary extract of Lavender oil has good evidence and a large effect size when used to treat GAD. In Germany there is a respect for the power of natural products, and they are regulated and prescribed in the same manner as pharmaceutical drugs. When silexan was studied in GAD the effect size can range from 0.5 to 0.9. This is a large effect size and I have another video that covers Silexan in detail if you are interested. This can be added to most medication regimens without significant drug interactions and has even been shown to decrease the use of benzodiazepines in those who are using them for GAD. It can be purchased under the brand Name Calm Aid for around $30 per month, and if you are wondering I get no financial compensation for saying this I’m just presenting the evidence.
Conclusion
We covered a lot here today and I think one of the most important points to stress is the importance of finding the underlying cause of anxiety symptoms. I believe anxiety is driven by other underlying factors as discussed at the beginning of the video. There are many reasons to be anxious and all require a different approach. Without this clarification the patient is likely to continue struggling. Another important point is theoretical mechanism of action that should work, do not always work as seen in the case of vilazodone. We also had some surprises, hydroxyzine, and silexan performed very well but traditional first line options such as SSRI and SNRIs were not so great. I hope this discussion was helpful and if you want more content on anxiety disorders, let me know below in the comments section.
Brain-Derived Neurotrophic Factor (BDNF) is a substance in the brain that promotes neuronal growth. It’s also involved in neuroplasticity in the developing brain. There is increasing interest in the role of BDNF in depression for several reasons.
We know that various brain structures are decreased in size in patients with major depressive disorder. Specific areas include the anterior cingulate, prefrontal cortex, and amygdala all of which are implicated in depression. Decreased serum levels of BDNF have been found in patients with depression and may be in part responsible for these changes.
Mutations to the BDNF gene have been associated with major depressive disorder (MDD). Antidepressant medications can increase BDNF, and in part may explain the effects of these medications.
