The diagnosis and treatment of attention deficit hyperactivity disorder (ADHD) is well established in the field of psychiatry. Not only is it well accepted, but ADHD has dramatically increased over the past 10 years. Some would even say it’s an epidemic in its own right. The use of psychostimulants as a treatment is common practice, and today we are here to discuss the risk of neurotoxicity with ADHD medication.
What Are Psychostimulants
Psychostimulants include methylphenidate (MPH) and mixed amphetamine salts such as Adderall. These remain the most effective and widely used medications for the treatment of ADHD. These medications function by blocking the dopamine reuptake transporter and increase dopamine stimulation at the postsynaptic receptors. These medications work to increase attention and reduce impulsivity but the long-term implications of consistent use are largely unknown.
Substance Use and Stimulant Prescribing
Most lines of evidence in the literature indicate that these medications do not promote substance use later in life and may even decrease the potential for future substance abuse. I’ve also found lines of evidence that indicate the opposite, but the general consensus in the field is that there is not increased risk for future substance abuse. We do know that drugs that function in a similar manner to these medications result in molecular and structural changes to neurons. It is unknown if this also occurs with stimulant medications used to treat ADHD.
Neuronal Effects of Amphetamine
Methamphetamine is a known neurotoxin and several studies have indicated this in animal models. Recently exposure to amphetamine has been sown to cause impairments on the development of dendritic branching up to 3 months after stopping methylphenidate. In mice there is evidence that MPH use causes loss of dopamine neurons in the substantia nigra which may increase the risk of Parkinson’s disease. Other groups have shown alterations in nerve growth factors and brain derived neurotrophic factor in the frontal cortex after chronic MPH use. When neurons from the prefrontal cortex are exposed to MPH it alters their electrical activity. MPH was found to reduce electrical activity and it persists in a dose dependent fashion even 10 weeks post exposure. In rats the use of MPH is associated with decreased response to normal stimuli and increased response to adverse stimuli. We need to be careful extrapolating this information to humans as these studies were conducted in animal models.
Treating agitation is a big part of inpatient and emergency psychiatric treatment. In the emergency department agitation accounts for 2.6% of total patient encounters. Knowing which medications to use and how to use them is critically important. Today I’m going to discuss all the options for the treatment of acute agitation in clinical practice.
What is Agitation?
Agitation is an extreme form of arousal that is associated with increased verbal and motor activity that poses a threat to themselves and others. Agitation needs to be recognized immediately and addressed due to the risk of harm to the patient and others.
Verbal De-escalation is Always The First Step
Engaging the patient and attempting to elicit a reason for the agitation should always be attempted first. In many cases patients are hungry, tired, or overly stimulated by the busy inpatient or ED setting. If these interventions are unsuccessful and the patient remains agitated security staff lead by the physician should inform the patient that if the behavior continues medication will be administered for safety purposes.
Thinking About Medication
Sometimes using medication is unavoidable and is required to facilitate a medical evaluation. We need to be mindful of the potential adverse events associated with sedating medication. The most common adverse effects are hypoxia, airway obstruction, QTc prolongation, bradycardia, and hypotension. Patients over the age of 65, alcohol intoxication, and multiple medication administrations in a short period of time increases the risk of adverse events.
Routes of Administration
It’s always best to offer PO (oral) medication prior to using IM or IV medications. In the inpatient setting we do not allow IVs due to the potential risk of self-harm; IM medication is second route of administration commonly used. I will usually use risperidone 2 mg or olanzapine zydis 10 mg because it begins dissolving immediately once the person puts it in their mouth in both cases. Oral medications can be “cheeked” and will also take longer to start working. In general, it’s important to note the onset of PO medication will be slower. Antipsychotic medications and benzodiazepines are commonly used for sedation in acute agitation.
First Generation Dopamine Blocking Medications
These medications have been around for a long time and have a good safety profile when used to treat acute agitation. Some antipsychotics have the risk for more side effects due to their ability to lower seizure threshold, cause hypotension, and have an increased anticholinergic burden.
Haloperidol
This is the go-to antipsychotic for acute agitation. It works by blocking D2 receptors and can be given PO, IM, or IV. Typical dosing is 2.5 to 10 mg with a recommended maximum dose of 20 mg/day. The average time to sedation is 25-28 minutes and the mean total time sedated is 84-126 minutes. The main risk for haloperidol is EPS such as acute dystonic reactions. To avoid this situation, we usually combine Haldol with lorazepam or benztropine/diphenhydramine. Haldol is also well studied and relatively staff for those who are acutely intoxicated with alcohol.
Chlorpromazine
I will usually go to chlorpromazine when I need someone to sleep such as cases of mania with acute agitation. I find it to be a little more sedating and it can be combined with diphenhydramine. Doses can range from 25 mg to 200 mg depending on the level of severity. The maximum dose is 400 mg/day.
Second Generation Dopamine Blocking Medication
Second generation medications have the added advantage of lower risk for QTc prolongation, less sedation, and fewer extrapyramidal symptoms compared to the first-generation options.
Olanzapine
Olanzapine comes in PO, IM, and IV forms, and the typical starting dose is 10 mg. Olanzapine reaches peak concentration in 15-45 minutes and its half-life is 2-4 hours. The incidence of EPS is much lower than injectable haloperidol. There is very rare incidence of QTc prolongation. There is some evidence that 10 mg of olanzapine is more effective than 5 mg of haloperidol for sedation and that most patients are adequately sedated at 15 minutes after administration of 10 mg olanzapine compared to 5 mg and 10 mg of haloperidol.
It’s important to note that multiple studies have demonstrated adverse events when olanzapine is combined with benzodiazepines. Although the risk may be overstated it’s best to avoid this combination unless necessary. Olanzapine is highly anticholinergic and should be avoided in cases where anticholinergic overdose is suspected.
Ziprasidone
Ziprasidone is a second-generation medication that is available in either PO or IM formulations. The PO form of the medication has little utility in acute agitation, but the IM version can be useful. Time to onset of effect is usually 15-20 minutes and it reaches peak concentrations in 30-45 minutes. The duration of sedation is at least 4 hours. Ziprasidone carriers the highest risk of second-generation medications for QTc prolongation
Risperidone
Data for risperidone in acute agitation is limitted. It does have the advantage of coming as an oral disintegrating tablet. In most cases I would administer 2-4 mg depending on the severity of symptoms. It can be a good option for patients with psychotic agitation due to paranoid delusions. It’s a good option for elderly patients and pregnant patients who can take PO medication.
Benzodiazepines
Benzodiazepines are another good choice when it comes to rapid treatment of acute agitation. Benzodiazepines do carry the risk of creating a paradoxical reaction in the elderly, but it’s relatively rare and seen in only 1% of cases. Flumazenil (benzodiazepine blocker) can be used to counteract this paradoxical reaction if needed. There is risk for respiratory depression especially in those who are already on central nervous system depressants. If withdrawal is suspected from benzodiazepines or alcohol, this is the first line option for treatment.
Lorazepam
Lorazepam is available in IV, IM, and PO formulations. The typical dosing is 0.5-2 mg IM or PO. This medication can be given every 30 minutes up to a maximum dose of 12 mg/day. Lorazepam is longer acting than midazolam and has an average time to adequate sedation of 32 minutes.
Midazolam
Midazolam is available in IM formulation and the typical dosing begins at 2-5 mg. The average time to sedation is 13-18 minutes for the IM formulation. When given IM the total time of sedation is between 82-105 minutes. Midazolam offers the advantage over lorazepam because it’s onset of action is faster. Midazolam also works faster than haloperidol or ziprasidone. The duration of sedation is also shorter.
Medication Combinations
In most cases these medications will be used in combination to maximize their effects. The most well-known is the so called B52 which consists of Haloperidol 5 mg, Lorazepam 2 mg, and diphenhydramine 50 mg. The idea here being 50, 5, and 2 are the doses and B52 because it’s like the B52 bombers when it comes to sedation. I also often combine chlorpromazine and olanzapine with 50 mg of diphenhydramine in the IM formulations. For PO risperidone you can combine it with PO lorazepam and diphenhydramine if needed. With ziprasidone I will usually give this one alone without lorazepam or diphenhydramine.
Physical Restraints
The utilization of physical restraints may be necessary when safety is a major concern. In some cases, verbal de-escalation, and medication are not enough. The problem is physical restraints can lead to injury for both the patient and staff. Patients who continue to fight against the restraints can have a complication known as rhabdomyolysis where the muscles are literally breaking down from the person fighting against the restraints. Sedation should always be provided when physical restraints are used. What happens if a person is given high doses of sedating medications and placed in psychical restraints but remains agitated?
Special Cases
It’s rare but I have had two clinical scenarios where an individual was placed in restraints given multiple doses of medications and remained severely agitated. Due to concern for the patient’s safety and risk of rhabdomyolysis I had to transfer each of these cases to the medical floor for IV dexmedetomidine (Precedex) which is commonly used to sedate patients in the intensive care unit who are intubated. After a short course of Precedex treatment each patient’s agitation resolved. There is now a rapidly dissolving film of dexmedetomidine available for acute agitation in bipolar disorder and schizophrenia, so I guess I was ahead of the times when I made these clinical decisions.
Conclusion
Agitation is a complicated and multifactorial process that requires quick action. To maintain safety, agitation needs to be quickly identified and managed. Verbal de-escalation and comfort measures should always be the starting point. If medications are required there are several individual and combinations that can be selected based on the clinical situation. When all else fails physical restraints remain a possibility until medications have had time to reach peak concentrations and effectiveness.
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.
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.
It wasn’t that long ago when I was sitting in lectures as a first-year psychiatry resident. I learned about the first- and second-generation antipsychotic medications in detail. One commandment that was always preached in my training was to never combine two antipsychotic medications because there is no additional benefit. Today we are here to explore this idea and see if there is truly no additional benefit to using two antipsychotics and explore why there is so much antipsychotic polypharmacy in serious mental illness.
Since most guidelines discourage the use of multiple antipsychotic medications, why are many psychiatrists going against these guidelines? In most cases we are just trying to stabilize patients, get them better, and keep them out of the hospital as the goal is to provide most psychiatric care in the community. To reach these goals a single medication does not always produce the desired results.
Patients that end up on multiple antipsychotics have some unique characteristics. They tend to have more severe psychotic symptoms, are male, unemployed, and younger. Those with frequent inpatient admissions on involuntary status are also more likely to end up on two medications.
What To Do When a Single Medication Is Not Enough?
The use of multiple antipsychotics is an area of limitted research. However, there is a difference between rational polypharmacy and irrational polypharmacy.
We should start this discussion by saying a patient should be started on monotherapy titrated to an effective dose and continued on the medication for 6 weeks prior to making a change. If the first medications fails, then switching to another medication or long acting injectable is a reasonable next step. If after another 6 weeks of treatment the patient remains unstable and symptomatic the technical next step is to start clozapine. There are many reasons why clozapine may not be a good option for a particular patient including the strict requirements for weekly complete blood cell counts CBCs.
Assuming this process is followed and the patient is still symptomatic what’s the next step?
Consider Receptor Binding Profiles
This is the first step in prescribing two medications rationally. Most first-generation medications such as Haldol will bind tightly to D2 receptors and stay bound to the sites longer. Second-generation medications like quetiapine are known to bind to the receptors and quickly dissociate giving an on-off like effect. Tight binding and longer duration of binding can lead to extrapyramidal side effects (EPS), whereas quick on-off medications like quetiapine have limitted EPS risk.
You should also consider other receptors the medication may target such as histamine and muscarinic cholinergic receptors. It would be best to avoid combining two medications that have high antihistamine and anticholinergic activity.
Let’s look at some scenarios where antipsychotic polypharmacy makes sense.
Patients With Acute Agitation
This is a common problem on the inpatient unit. A patient is on a low-potency quick on-off medication like quetiapine but remains symptomatic and is engaging in dangerous behavior.
The addition of a higher potency, higher affinity medication like Haldol makes some sense here. This will control the acute agitation, can be titrated until the psychotic aggression is controlled, and can be stopped as soon as the patient is stable on quetiapine. We can see how the receptor binding profile makes this combination reasonable.
Clozapine Refractory Patients
What do you do when a patient is on the best antipsychotic medication but remains symptomatic?
We do have several lines of evidence that we can look at for this question. One option is to add low dose risperidone. This is a similar idea to adding Haldol to quetiapine. Clozapine has lower affinity for the D2 receptor than risperidone which has much higher affinity for D2 receptors. There were two placebo-controlled trials that support this combination. Before combining medications, I would suggest obtaining a clozapine level to make sure it’s therapeutic.
There are two more recent studies that compared multiple antipsychotic medication combinations and used rehospitalization as a measure of effectiveness. Both studies found a significant reduction in rehospitalization for patients receiving polypharmacy compared to those receiving monotherapy. The best outcome was achieved when clozapine was combined with aripiprazole.
Patient is On a Long Acting Injectable (LAI) but Remains Symptomatic at the Highest Dose
This is a common problem because the doses of LAIs are limitted. For example, the LAI aripiprazole (Aristida) is limitted to a maximum dose of 20 mg/day. The oral formulations of aripiprazole allow for a maximum dose of 30 mg/day. One strategy is to give the injection early. This will usually be done on week 3 for formulations that last 4 weeks. Another option is to add another medication with a different receptor binding profile such as the clozapine aripiprazole combination that was shown to reduce the risk of rehospitalization.
Treatment of Insomnia
The addition of low dose quetiapine to a medication like paliperidone is common in clinical practice. Once D2 receptor blockade has been maximized by reaching an effective dose of paliperidone, considering the addition of as need (PRN) quetiapine for its low potency and sedating properties is reasonable. The medication should be used PRN only and should be removed once the insomnia has resolved. Consider a sleep study if sleep apnea is possible and using other options such as short-term orexin antagonists, melatonin, and sedating antidepressant if appropriate.
Treatment of Antipsychotic Induced Side Effects
I know what you are going to say, adding a medication to treat a side effect of another medication doesn’t make sense. Let’s take an example to illustrate why this makes sense. If a patient is stable on risperidone and is discovered to have an elevated prolactin level you have an obligation to address it. The addition of low dose aripiprazole has been proven to reduce prolactin levels in these cases. Another possibility is using aripiprazole to reduce the metabolic burden of medications such as clozapine. There is much more limited data in this area and I would consider metformin a much better option to start with if antipsychotic induced weight gain is a problem.
In the process of Switching Medication the Patient Achieves Remission
This is another common clinical scenario. A patient didn’t respond to a medication, and you begin decreasing the dose of the first medication while titrating the new medicine. Then suddenly they are better. You don’t know why but they are better than they have ever been and now you are afraid to make any additional changes. Ideally you would finish the process and appropriately titrate the new medicine while discontinuing the ineffective medication. There is no good data to support inadequate dosing of two antipsychotics, and it’s best to continue your taper/titration and reevaluate after it’s complete.
Conclusion
There is still limited data to support the use of multiple antipsychotic medications although it is often seen in clinical practice. There are a few places where the addition of a second medication makes sense, and we can use receptor profiles to help us make rational decisions and avoid excess side effect burden.
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.
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.
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.
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.
Anxiety is pervasive in the world today. All of us including me know what it’s like to be anxious. We have all read recent articles about how the COVID-19 pandemic increased anxiety around the world, and this has placed a lot of focus on anxiety as a psychiatric diagnosis. Anxiety in my opinion is not an independent disease the way the diagnostic and statistical manual (DSM) would lead you to believe. Anxiety is a symptom that has various potential causes and that’s what we are here to talk about today.
This is inspired by a real case where I needed to do a deep drive into the literature to understand the root of anxiety and its treatments. I hope you guys enjoy the topic.
Introduction
Generalized Anxiety disorder has been revised significantly over the years by the DSM. It seems like no one knowns what GAD is, or if it’s an independent disease state. The DSM only provides descriptive criteria and does not comment on the underlying cause of anxiety. Prior DSM criteria from DSM III focused more heavily on autonomic and motor symptoms of anxiety. In these editions, what is now GAD was referred to as psychoneurosis an old Freudian term that fell out of favor as we moved away from psychoanalysis. Interesting fact, if you look up the indication for hydroxyzine in anxiety it still states “for tension associated with psychoneurosis.” The more recent updates in DSM have stepped away from these physical symptoms and focused more on the mental state of chronic and excessive worry. If we attempt to apply older studies on anxiety treatment to the current DSM criteria, they may not be valid.
What I want to stress, is worrying is the core symptom of GAD now with at least 3 out of 6 of the following:
-Restlessness
-Being easily fatigued
-Difficulty concentrating
-Irritability
-Muscle tension
-Sleep disturbance include insomnia
When I look at the criteria, they look a lot like depression to me. I often argue to my residents and medical students that it’s hard to separate depression and anxiety, but they usually disagree, so this video is for them as well.
Causes of Anxiety
We should try and figure out what the potential underlying causes are for anxiety. Since the DSM does not guide us here, we need to think through each possible cause.
Personality: people often underestimate the importance of personality traits in psychiatry. One personality trait that is part of the “big 5” is neuroticism. We all have anxiety as a personality trait, some individuals have more some have less, but for the most part there is a normal distribution in the population. If you have more, you tend to get diagnosed as having a “anxiety disorder.” Most people fall in the middle we have some anxiety under specific circumstances but not enough for it to be identified as pathology.
Depression: As I stated before there is a lot of overlap in the criteria for depression and generalized anxiety disorder. In fact, the same medications are used to treat both disorders. Depression can clearly be a cause of anxiety.
Mania: people often mistakenly believe that people in manic states are having fun and love being that way. This is not true, and anxiety can be one of the potential symptoms associated with manic states.
Psychosis: Schizophrenia or schizoaffective disorder can be anxiety provoking disorders
PTSD: Excessive worry can be a part of PTSD
Eating Disorders
Substance Use Disorders
OCD
Other environmental factors can cause anxiety independent of those listed above: life stages, divorce, death of a loved one, diagnosis of severe physical illness, significant loss of physical function from an injury
The point here is there are many things that could result in a state of high anxiety. What you should start to see here is once we rule out all these causes for anxiety there would be no way to diagnose an independent anxiety disorder.
Just describing the symptoms of anxiety checking the boxes for the criteria and labeling someone as having “anxiety disorder” does not have much meaning. We have to say what the underlying cause of the anxiety is to treat the symptoms effectively.
Myths About Medication in Anxiety Disorders
People often believe that anxiety responds faster to medication than depression. This is not true the response to medication takes the same amount of time for both anxiety and depression. This provides another layer of evidence that GAD can be driven by depressed states. Trials of medications such as SSRIs can last several weeks as doses are titrated until the individual has an acceptable level of response to the medication.
There is also no established dose dependent response in GAD. Some believe that GAD responds better to higher doses of SSRIs, say 40 mg of escitalopram. This has not been established in the research literature. This may also indicate that the underlying cause is OCD which traditionally requires higher doses and longer duration of treatment.
Many people presenting with anxiety will be started on an SSRI. In the past paroxetine was favored by primary care because it had the FDA indication for use in anxiety disorders. I never think paroxetine is the correct choice for anxiety due to the side effect profile which includes risk for withdrawal and harm during pregnancy. Citalopram has suffered a similar fate as dose dependent QTc prolongation limits the doses we can use in clinical practice. Escitalopram can prolong QTc at higher dose above the approved maximum but there is significantly less risk at standard doses.
How effective are these medications for anxiety disorders? Not very, a meta-analysis found that SSRIs have an effect size of 0.33 falling into the low range.
Part Two:
Part two of this series will be coming soon. I had way too much to say about the diagnosis of GAD that I didn’t leave any time to discuss treatment. Part two will included a detailed analysis of medications for GAD.
