Why People with Major Depression Don’t Get Better 

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. 

Jonah Hill’s Netflix Doc: ‘Stutz” 

Recently Jonah Hill celebrated the gift of therapy with his Netflix documentary ‘Stutz’ which chronicles his journey through therapy and his friendship with Phil Stutz co-author of The Tools. This film was intended to highlight the benefits of psychotherapy and celebrate the teachings of Dr. Stutz. Personally, I think the documentary was low on practical advice for the average person, but it did highlight one very important factor that affects therapy outcomes. That will be the topic of today’s video, can we have a therapist who is also our friend?

Therapeutic Alliance and Why It’s so Important 

This documentary raises many questions for someone who has been in both roles as therapist and patient. Time and time again we see that the most important factor in psychotherapy outcomes is the strength of the therapeutic alliance. The therapeutic alliance is a working relationship between the patient and their therapist that allows them to work together on established goals of therapy. 

To me this comes down to how much do you like, trust, and feel comfortable opening up to the therapist. When we like someone and feel-good talking to them, we feel better regardless of what type of therapeutic techniques they use. Research has suggested that the quality of this relationship is a reliable predictor of positive clinical outcomes independent of the psychotherapy approach used. I remember in training hearing many of my psychotherapy preceptors make similar statements. Jonah Hill did a wonderful job of demonstrating the power of this alliance throughout the film. For me this was the big takeaway, considering Stutz is not a traditional psychotherapist.

Having a Therapist as Your Friend

I do not believe it’s ever a good idea to become friends with a patient. There are reasons we do not accepts gifts from patients, hangout with them outside of the assigned appointment times, or have romantic relationships. These to me are boundary crossings which will interfere with the work. Yes, in the case of this film it all worked out fine, at least that’s what they want you to believe. It did not appear that Hill had fully come to terms with his past, or unstable self image. He still seemed vulnerable and is possibly worse off as he’s come to depend on the relationship with Stutz for relief.

The goal of any good therapist should to teach our patients to become their own therapist. To use and apply the skills learned in the work of therapy, not to come for some friendly advice or a chat like old college buddies. The therapist is there to help guide the work in a warm empathetic way that allows the patient to take control of their life.

What Makes Stutz a Good Therapist?

It’s very difficult to make a blanket statement about how good Stutz is as a therapist. For Hill, he helped him process some very difficult work including making peace with his brother’s untimely death and working on self-esteem and body image. Stutz is honest, warm, and empathetic during his encounters. He knows how to push sensitive buttons in a playful manner and can establish a strong therapeutic alliance. These are things any aspiring psychotherapist can and should learn to use.

Some Things That Are Not So Good

When you start psychotherapy with any patient you must establish a therapeutic framework where the work of psychotherapy will be carried out. While I believe there is a loose framework established in the film it doesn’t appear to be well developed. This opens the door for boundary crossing which you as the therapist might not be aware is occurring because the frame is so weak. He also relies on self-developed Tools that aren’t validated by scientific evidence and appears at times as an authority figure giving out life advice. Advice can be useful in supportive psychotherapy, but most patients will not follow advice alone. Is this entirely bad? No, but it might not work for most patients unless you share the same feelings for the therapist as Hill does. 

Therapist Reputation and Outcomes 

Sometimes a therapist will develop a reputation as being “good.” Clearly, in celebrity circles Stutz has that reputation. When a new patient comes there is a belief that this therapist has access to special knowledge or skills that cannot be had any other way is already established. I do not think the tools as presented in the book/film are groundbreaking or things people have not heard before. In the film Stutz words are seen as absolute truth and there is full buy in from Hill which is probably why he felt better. While his tools are developed from his clinical practice, they are not validated scientifically. In place of science, we have a charismatic therapist asking for full faith in a program with no scientific validity. For some this approach clearly works, but it’s not because the tools are any better than other techniques used in psychotherapy. 

Final Thoughts

I really Like Stutz and I do believe there are people that would benefit from his approach to therapy. However, the main benefit would not come from the tools he teaches because they are largely similar to other techniques and not scientifically validated. What you would benefit from in this brand of therapy is a warm, emphatic, and charismatic listener with some good advice if you’re willing to take it. After all, maybe that is really where the magic of therapy comes from anyway.

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. 

Take Your Pills: Xanax What They Got Right 

As many might know there is a new Netflix documentary called Take Your Pills: Xanax and it combines interview footage from physicians, patients, and journalists about anxiety and the use of Xanax. For the most part I thought there were a lot of reasonable discussions about anxiety, its treatment, and the role of medication. I feel like this is an appropriate way to cap off our recent discussions about anxiety disorders and treatment. 

Fear and Anxiety: Are They the Same Thing? 

The documentary made it seem like anxiety and fear are the same thing and that the exact same neurobiology is involved in each case. I think about anxiety and fear as two separate things that require different approaches. 

Anxiety is what an individual feels when they are worried about something that could potentially happen in the future. If you watched my other videos on generalized anxiety disorder (GAD) then you know the Diagnostic and statistical manual (DSM) has made excessive worry the hallmark of GAD.

Fear is a core emotion along with sadness, anger, joy, excitement, and disgust. It’s different than anxiety, which is a fear of some future event happening. Fear is triggered in the moment. When you see that bear walking on the hiking trail or hear the rattle of a snake the fear centers of our brain are activated immediately in that moment. It’s not that we are obsessing about some future outcome, there is something present in the environment that is threatening and demands immediate action.

The Fear Center of The Brain

In humans the fear center of the brain is called the amygdala which stands for almond and that’s because they taste like almonds. No, wait that isn’t right, it’s because they are shaped like an almond. The amygdala is what fires when you see that bear in the woods. This triggers the fight or flight response which leads to things like increase blood flow to the muscles, and increased energy. It prepares the body to run away or fight if necessary. 

Benzodiazepines MOA

Benzodiazepines enhance GABA activity by acting as allosteric modulators of the GABA-A receptors. This is the major inhibitory neurotransmitter in the body, and it acts to dampen everything down. Benzodiazepines increase the frequency of opening of chloride ion channels which in turn inhibits the cell and prevents the neuron from firing. 

Anxiety Is a Part of Life

As I’ve said before we all have anxiety under certain circumstances. It’s not always a bad thing to have anxiety. In many ways anxiety reminds us that this situation is important, and we need to be appropriately prepared. A healthy amount of anxiety is a good thing overall. 

Things go sideways when the anxiety is chronic, persistent, and severe. As I’ve stated in the previous videos some people are just more prone to anxiety. These individuals are high in the big 5 personality trait of neuroticism. While most of us will fall somewhere in the middle there will be outliers on either side with some having significantly less anxiety and others having significantly more.  

The one thing that made this documentary hard to follow is that they combined all the anxiety disorders together, at one point they were describing panic attacks, social anxiety, and GAD as if they are all part of the same disease process. While there is significant overlap, the course of illness, and treatment plans will vary greatly which is why proper diagnosis is so important. 

Xanax Works great for Physical Symptoms of Panic Attacks 

When the interviewees start talking about Xanax it’s in the context of people experiencing panic attack. This is an important distinction to note as most of the symptoms of panic attacks are physical and thus will have a greater response to benzodiazepines. If we are talking about GAD, or social anxiety the anxious thoughts will still be there, and the benzodiazepine may be less effective. 

Why Temperament and Environment Deserves More Attention 

Much of our baseline temperament is genetic and will be part of the story that determines if you will have more or less anxiety. The other part of the story is environment. The experiences we have matter a lot too. In child psychiatry, there has been this huge focus on minimizing adverse childhood events (ACES). We discovered that things like sexual abuse, physical abuse, and loss of a parent can result in significant risk for poor health outcomes in the future. Baseline temperament that predisposes someone to anxiety combined with significant lifetime trauma could set the table for a future anxiety disorder. 

The Prevalence of Benzodiazepine Use 

In this documentary they make it seem like benzodiazepine prescriptions have skyrocketed over the last several decades. These prescriptions have increased but we need to explore why. One thing I see all the time is primary care providers prescribing benzodiazepines for patients early in treatment for depression and anxiety. Before exploring psychotherapy or other medication options the person walks out with a Xanax prescription. There is a reason the research tells us most people who see a primary care provider for depression and anxiety do not get better. In fact, as few as 20% of those started on antidepressants by primary care will show significant clinical improvement. This is not a knock on primary care, it’s more that they have been thrown into a mental health crisis and are usually the first person to encounter a patient with anxiety. 

The important trends I would like people to pay more attention to is the risk of prescribing opioids and benzodiazepines in combination. This can result in increased risk for overdose death and a significant risk for severe respiratory depression. In addiction treatment people often feel very anxious when stopping opioids and it’s common to want to address that anxiety as a doctor. What ends up happening is people are on medication treatment for opioid use disorder, a benzodiazepine for anxiety, and gabapentin for that little extra relief. All these medications in combination put the patient at risk for adverse outcomes. Another thing to pay attention to is where all the opioid prescriptions are coming from. The highest rates are in many southern states and in places like West Virginia where the opioid epidemic hit the hardest. The final item to discuss is the increased rates of benzodiazepine prescribing in the elderly. There seems to be an increase in benzodiazepine use in this population which is more dangerous due to the risk of falls, altered mental status, and possibly dementia. 

There has been a lot of talk over the years about the increased risk of dementia associated with benzodiazepine use. There data has been mixed, but I would say it’s largely in favor of using caution when prescribing benzodiazepines in older populations and avoiding the long-term use of benzodiazepines in all populations.

Social Media and Anxiety 

I think social media has done as much harm as it has good for people’s mental health. If you believe everything you see on social media, the impression is everyone you know, or follow is winning, and you are losing. In the past you only had to compare your life to people in your community. Now, we get to compare our lives to the world. Not only are we comparing our lives to large pool of people, but we are also comparing them to people who have created online personas under false pretenses. These are individuals rent house for photo shoots to make you believe that is where they live, or people taking steroids then asking you to buy some supplement that does not provide the results it promises. We all like to think we are immune to these types of schemes, but we are not. In our minds we are comparing our worst moments to other people’s best moments and assuming that this is reality. This is clearly a recipe for anxiety and depression. 

Dangerous Coping Strategies for Anxiety 

I do not think using alcohol or drugs to alter one’s state of consciousness is exclusive to the past. People have been doing this forever, and it remains a poor way to cope with anxiety. I think one of our problems is attempting to cure the stresses of life. In my practice I do not believe that taking a medication or using alcohol are ways to “cure” anxiety. Most individuals need to take a long hard look at their life and see where the anxiety is coming from and where life changes can be implemented to reduce the tension. When someone takes time to systematically dissect the cause of their anxiety, they often already know what they should do. Take more time off work, practice better self-care, exercise, eat healthy, and sleep better these examples all come to mind for most patients. Most people feel trapped and do not believe they can carve out the time to do these things and that is part of the reason they turn to medication or drugs/alcohol to cope. 

While I still believe benzodiazepines can be useful in the right context, they are designed to be used short term. I set limits with my patients early in the process letting them know up front that we are not using this as a long-term solution for their anxiety. 

Potential Side Effects of Benzodiazepine use 

They did a nice job of describing the changes in memory that occur because of benzodiazepine use. The ability to laydown new memories is impaired when using benzodiazepines that is why I caution anyone with PTSD who is in trauma-based psychotherapy to avoid the use of benzodiazepines. They also focused on the disinhibition caused by increased GABA-A activity. This is less a side effect and more a response that should be expected from the medication. Most individuals with anxiety are wound too tight and have trouble relaxing. The problem with this response occurs when that disinhibition is excessive resulting in embarrassment or inability to work for example. 

Withdrawal from these medications can be deadly. There is risk for seizure, rebound anxiety, rebound insomnia all of which can be very distressing. The problem with benzodiazepine withdrawal is the variability in terms of patient’s tolerance to dose reductions. Some patients can tapper off very quickly and have no issue, others need to be tapered slowly over months to years. While I would say it’s rare to have someone who is very sensitive to dose adjustments it can happen and tapering slowly while watching for withdrawal symptoms is important. The example of the guy pipetting a liquid microdose of alprazolam would not be a normal situation, and if you just watch this documentary, you may think everyone who tries to come off these medications must go through a similar process. Benzodiazepines can be safely reduced under the guidance of doctor. 

Conclusion

What we see in the end is more of the same recommendations most of my patients would tell “doc I already know this.” They talked about using complementary and alternative medicine which I am a big fan of, diet, exercise, mindfulness, and psychotherapy to find the underlying causes of the excessive worry. They introduce the idea at the end that the world is broken and defective and we should not have to accept the world as it is. This is fine but significant change on a massive scale takes time and it still leaves people asking the question “what do I do right now.” I’m personally active in advocacy work at the local and state level, which is one approach, but it takes a lot of time and resources to affect policy changes and not every patient will have the time or desire to engage in such activities. The only true way out of anxiety is through it. Daily life is painful, and we need to accept that to some degree. Medicating away feelings that are part of life is certainly not the solution and can be the reason we find ourselves in trouble. 

The Truth About Anxiety Treatments: What Really Works 

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. 

Does Everyone Have Autism or Is It Just Me? 

There is an ongoing fascination in the world of social media with regards to certain psychiatric diagnoses. It begins with the rise of self-diagnosing, which is rampant on social media these days and ends with a lot of individuals believing they have autism, tic disorder, or dissociative identity disorder (multiple personalities). I’ve also seen a rise in my patients suggesting they have autism as an explanation for symptoms clearly caused by other disorders. 

I can think of one specific example where an individual was convinced, they had autism. Later that day I observed the individual socializing with peers and staff making excellent eye contact, and all those symptoms they described in the diagnostic interview seemingly went away completely. It was clear at that point that autism was not the cause of this individual’s distress.

I feel like there is no better time to discuss autism spectrum disorders because we have a lot to clear up. 

Introduction

Autism spectrum disorder (ASD) was introduced in the diagnostic and statistical manual (DSM-5) to replace the category of pervasive developmental disorders (PDD) which previously included Asperger’s disorder, Autistic disorder, and PDD not otherwise specified (NOS). You might ask, why did they change the category in DSM-5 to just autism spectrum disorder? This was thought to improve the ability to make a diagnosis of ASD while maintaining the sensitivity of its criteria. In fact, research suggests that 91% of those who met the previous criteria would meet the new DSM-5 criteria. They also grandfathered in those with a previously well-established diagnosis of Asperger’s, autistic disorder, or PDD NOS. 

Epidemiology

In 2021, the CDC reported that approximately 1 in 44 children in the U.S. is diagnosed with ASD. The prevalence has been rising over the years, and this is largely thought to be related to better detection and awareness of the disorder not vaccinations or other environmental factors. ASD is 4.5 times more common in males than females. The median age when ASD is diagnosed in the U.S. is 50 months which is about 4 years of age. ASD can be found in all racial and ethnic groups although the prevalence does appear to be higher in Caucasian children. 

Clinical Features of ASD

The focus in DSM-5 was in two domains and not the three domains from the prior classification. These domains are social communication impairment and restricted/repetitive patterns of behavior, and an individual must have had these symptoms in early childhood. Specifiers were added to indicate the level of impairment, level 1: requiring support, level 2: requiring substantial support, and level 3: requiring very substantial support.

DSM-5 Criteria 

Persistent deficits in social communication and social interaction, as manifested by all 3 of the following:

-Deficits in social-emotional exchange: failure of back-and-forth communication, reduced sharing of interests, emotions, or affect, or failure to respond to social interactions. 

-Deficits in nonverbal communicative behaviors used for social interaction: difficulty understanding facial expressions, body language, or eye contact 

-Deficits in developing and maintaining relationships appropriate for the developmental level: difficulty adjusting behavior based on social context, difficult engaging in imaginative paly, or difficulty making friends 

These symptoms can be seen in other disorders in the adult population including social anxiety, OCD, schizoid personality disorder, schizotypal personality disorder, avoidant personality disorder, schizophrenia, bipolar disorder, and intellectual disability. Therefore, it’s important to establish that these deficits were present at an early age. 

Restricted, Repetitive Patterns of Behavior, Interests, or activities 

At least two of the following must be present:

  • Stereotyped or repetitive speech, motor movements, or use of objects (simple motor stereotypies, lining up toys, or repetitive use of objects). 
  • Insistence on sameness, inflexible adherence to routines, ritualized patterns of verbal or nonverbal behavior, or excessive resistance to change 
  • -Highly restricted, fixated interests that are abnormal in intensity or focus 
  • -Hyper-or hypo-reactivity to sensory input or unusual interest in sensory aspects of environment 

These individuals may have a rigid greeting ritual or struggle with small changes to normal activity. I had a case where the family took a different route to school one day and child became so upset that they jumped out of a moving car. This is the level of insistence on sameness and routine that we are talking about. 

Gender Impact on ASD

The prevalence of ASD is lower in females, but females are noted to have a greater impairment in social communication, lower cognitive abilities, and more difficulty externalizing problems than males. 

Causes of ASD

ASD is a complex neurodevelopmental disorder with both genetic and environmental factors. Family and genetic studies identified ASD as a highly heritable disorder. The heritability can range from 37% to more than 90% with only 15% of cases being attributed to a known genetic mutation. ASD is polygenic meaning there are multiple genes that contribute to the disease. Many inherited genetic variants contribute to a small additive risk of developing ASD. 

Neuroimaging research has found that ASD is often associated with atypical brain maturation. Children with autism usually have an excessive number of synapses in the cerebral cortex, this indicates abnormal pruning may be part of the etiology. Pruning occurs at a critical period in childhood where excess synapses are eliminated, it’s critical for proper cortical maturation. Other findings include abnormalities in neurotransmitter levels, immune dysfunction, and neuroinflammation. 

One of the greatest areas of controversy has focused on the impact on childhood vaccinations as a causative factor for ASD. The current evidence does not support this theory, and ASD is not associated with childhood vaccinations. 

Environmental factors including exposure to valproate, air pollution, low birth weight, and increased maternal and paternal age are all associated with increased risk for the development of ASD. 

Co-Morbidity

The most common co-morbid disorders in ASD include intellectual disability, ADHD, and seizure disorder. Approximately one-third of individuals with ASD meet criteria for intellectual disability. ADHD can be seen in 30% to 50% of individuals with ASD. Seizure disorders in these individuals can be difficult to treat, and often refractory to treatment. There is also increased risk of gastrointestinal disturbances such as constipation and restricted food intake.

Evaluating Someone with Suspected ASD

The assessment of ASD requires both an evaluation of the individual and collateral information from caregivers and teachers. ASD remains a clinical diagnosis, but there are several screening and diagnostic assessments that may help support the diagnosis. The most well-known is the ADOS autism diagnostic observation schedule, and the ADI-R autism diagnostic interview revised. 

A delay in spoken language is common first symptom that prompts referral in younger children for autism screening. The starting point is usually to check hearing and vision to be sure the individual is not suffering from deficit in either of these sensory domains. If there are dysmorphic characteristics, genetic testing for specific genetic disorders may also be completed prior to the evaluation. 

Treatment

There is no FDA approved medication for the treatment of ASD. The primary intervention is behavioral, and these interventions should be started as soon as possible. Applied behavioral analysis (ABA) is a type of therapy that focuses in developing specific behaviors such as social skills, communication, reading, and academics as well as fine motor dexterity, hygiene, grooming, domestic capabilities, and job competence. This should be the core of treatment and has good evidence to support its use. 

If medications are used, it’s important to note that they do change the underlying communication or social deficits seen in these children. They are used to target specific co-morbidities such as ADHD, or symptoms that include irritability and aggression. There are only two FDA approved medications for ASD-related symptoms. These medications are risperidone, and aripiprazole and they are approved to treat irritability in children. 

Conclusion

ASD is a complex disorder with multiple genetic and environmental factors contributing to the development of the disorder. Since it’s a neurodevelopmental disorder it’s often present at an early age and suspicion of ASD should be followed up with a proper diagnostic evaluation.  I think it’s important for people to avoid self-diagnosis and be careful what information they are consuming on social media. 

   Why It’s Important to Thrive and Not Just Survive

We Spend a significant amount of time as doctors monitoring for adverse outcomes. 

We use the absence of disease as an indicator of health. 

But the mere absence of disease is not enough to proclaim good health. 

If we only monitor for the absence of disease, we miss the things that are most important in our patients’ daily lives. 

The things I’ve found to be most important in my life, and often lacking in my patient’s lives are…

Being happy, having a sense of purpose and meaning, and having good relationships which are sometimes ignored if overt signs and symptoms of disease are not present. 

Being “well” is a state of complete mental, physical, and social wellbeing. 

Having a purpose in life is associated with reduced mortality risk, so is life satisfaction. Things like loneliness and social isolation are associated with increased mortality.

When these needs are met people not only live longer but they live with intention. 

Let’s Look beyond the absence disease 

Guide To Viewing My Content

If you are new to the blog and my social media content, we should start with a brief introduction. 

My name is Dr. Garrett Rossi, I’m a medical doctor who specializes in adult psychiatry. I’m board certified by the American Board of Psychiatry and Neurology. I’ve practiced in multiple settings including inpatient, outpatient, partial care, assertive community treatment teams, and I provide ECT services.

I make mental health content on multiple social media platforms and each one has a specific style and type of content. 

Shrinks In Sneakers YouTube Click Here

This is where you can find the deep dives on mental health topics including medication reviews, psychiatric diagnosis, and various other topics. Videos can range anywhere from 5-20 minutes and time stamps are available in the descriptions for longer content. 

Shrinks In Sneakers Instagram Click Here:

This is where you can find shorter videos and posts on mental health topics. The focus on Instagram is more on mental health advocacy, and myths about psychiatry and mental illness. The content here is shorter but still has a lot of educational value. 

Shrinks In Sneakers LinkedIn:

This is where you can find more information about my professional activities. I have information about my advocacy work, professional memberships, publications, and is another good place to follow my work. I make frequent posts here as well. 

Shrinks In Sneakers Twitter

Here I’m not very active and haven’t spent much time but I do update blog posts and other relevant information here as well. 

If you have a question or want to get in touch with me, I am most active on YouTube, LinkedIn, and Instagram. 

We are building a community where empathy is a central part of the content. The goal is to make psychiatry more accessible, provide education, and reduce stigma associated with mental health treatment. 

Diagnosis Depression: Sleep Dysregulation

One of the most common symptoms found in multiple psychiatric disorders is sleep disturbance. In fact, sleep disturbance is one of the criteria for the diagnosis of major depression. This post will offer an explanation of some of the changes observed in the sleep patterns of depressed patients.

Much of this information comes from sleep studies in patients who have a diagnosis of major depressive disorder. Without getting too technical there are two primary types of sleep, non-rapid eye movement sleep (NREM) and rapid eye movement sleep (REM). The NREM sleep can be broken down further but for the sake of simplicity we will consider these two categories. 

What we notice in sleep studies of patients who suffer from major depression is a much faster onset of REM sleep. The body usually cycles through these stages 4-6 times throughout the night, averaging 90 minutes in each stage. As the night progress NREM sleep decreases and REM sleep increases. A person with normal sleep architecture will enter REM after 90 minutes, in patients with depression this time period is shorter and can be observed on the sleep study results.

Other changes include decrease NREM sleep which can be thought of as restorative sleep. Increased REM density reduced total sleep time, and decreased sleep continuity are also present. 

Any single change in sleep architecture is not diagnostic of major depression. However, taken together decreased onset to REM, increased REM density, and decrease sleep efficiency can separate patients with major depression from a control group. 

Given all of this information, routine sleep studies are not diagnostic for major depression and are not routinely ordered unless you suspect another sleep disorder. 

Hopefully this provides a basis for why questions about sleep in depressed patients are important. The sleep changes also provide some objective evidence of altered sleeping patterns in patients with depression. 

Is Depression A Genetic Disorder?

Introduction:

This is a common and difficult question I get asked. Like everything in psychiatry, the answer is not clear.

When people think about genetic disorders, they tend to think about classic genetic diseases. Some examples would be sickle cell anemia or cystic fibrosis. There is a clear pattern of inheritance with a single gene involved in these diseases

The human genome project set out to sequence the entire human genome. While it accomplished the goal it did not offer the personalized medicine and targeted interventions initially promised. What it did reveal was a more complicated interplay of genetics and environmental factors. Depression is a multifactorial disease and does not have a single gene involved in the disorder. 

Let’s look at some the evidence supporting the genetic influence on the development of depression.

What Can Family studies tell us ?

The first place to look for a genetic link is family studies. This is one reason we obtain a family history in a psychiatric interview.

MDD is common in families. It’s found 2 to 3 times more often in first-degree biological relatives (e.g. mother or father) of individuals with the disorder than the general population. It’s important to note that the influence of genetics on the development of depression depends on the percent of the genome shared by the individuals. For example, first-degree relatives who share 50% of their genome will have a much greater influence than a second-degree relative who shares 25% of the genome.

What can twin studies tell us ?

The second area of evidence that supports the influence of genetics on depression comes from twin studies.

From the data we know for monozygotic twins (identical twins), there is a 50% chance that one twin will develop the trait (e.g. depression) if the other twin has depression. This number decreases to 20% for fraternal twins who only share 50% of their genome. One flaw in many of these studies is the twins were often raised together in the same environment. There is clearly something to be said for the influence of environment. Some researchers believe twins will influence each other’s behavior when raised together. Identical twins have been known to be treated more similar by their parents than fraternal twins. Taken at face value, when a twin with 100% of the same genetics (identical twins) develops depression the other twin is more likely to also develop depression. Keep in mind, they do not always develop depression even if they share 100% of the genome. 

What do adoption studies add?

Adoption studies make an attempt to differentiate the influence of genetics from environmental factors. These studies examine differences in rates of illness among biological relatives as opposed to adoptive relatives. The studies show higher rates of illness among biological parents rather than adoptive parents. This provides some additional evidence to support a genetic influence. 

Conclusion

There is clearly a genetic component to depression. However, it’s a complicated process that involves multiple genes interacting with the environment. This makes identifying a single causal gene difficult and likely impossible. There are people biologically predisposed to developing depression, but not everyone with biological predisposition will go on to develop depression. 

If you found this helpful please like, comment and share your thoughts for future posts on genetics.

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