Shrinks In Sneakers

Tag: mental health treatment

  • SAINT The Best Transcranial Magnetic Stimulation (TMS) Therapy Protocol Ever  

    SAINT The Best Transcranial Magnetic Stimulation (TMS) Therapy Protocol Ever  

    We all know how difficult treatment resistant depression (TRD) is for both the patient and the clinician. Wouldn’t it be great if we had a noninvasive method to treat these cases with better efficacy than ECT? What if I told you there is a new type of TMS that leads to remission in 80% of the most difficult to treat cases of depression? Would you be interested? Let’s Find out. 

    Introduction:

    SAINT stands for Stanford Accelerated Intelligent Neuromodulation Therapy, try saying that one three times fast. 

    This is not a new concept as SAINT uses a noninvasive neuromodulation therapy (TMS) in patients with treatment resistant depression and it has shown some real promise in that area.

    Treatment resistant depression (TRD) can affect up to 30% of patients with major depressive disorder and as you might expect it’s hard to treat these cases. When a patient reaches this point, things like off-label medication prescribing, ECT and Ketamine are used. However, the FDA just approved a new version of TMS that is reported to have an 80% remission rate in these patients. 

    The approval came quick as this device has received breakthrough status by the FDA based on the impressive results from study that included 22 participants with TRD. 19 of the 22 participants achieved remission which in terms of percentage was 86.4% of participants. This is substantially better than other treatments for TRD including ECT which come in around 50%-70% depending on the study you read. 

    What Is SAINT?

    SAINT was first developed at Stanford University. What sets this TMS procedure apart from other methods of TMS is the intensity of treatment (10 sessions per day) carried out over the course of 5 days. Each session is 10 minutes in length. The intelligent portion of the name has to do with the use of MRI/fMRI-guided theta burst stimulation ensure proper placement of the coil on the dorsal lateral prefrontal cortex. 

    This device made it out of the academic arena and is now being distributed by a private start up company called Magnus Medical. You can get on the waiting list now to purchase one of these machines if you feel compelled to do so after this talk. To be clear I have no affiliations with the company.

    What Research Lead to FDA Breakthrough Status Approval?

    In general devices are not held to the same standard as medications when we are talking about FDA approval. It’s much easier to get a device approved. 

    The initial work was carried out with an open label format which is usually considered a lower form of evidence when compared to randomized controlled trials. The research group eventually published a randomized controlled trial in the American Journal of Psychiatry which is largely what allowed SAINT to gain FDA approval. In this study 32 participants with TRD were randomized to active treatment or sham. In this study they used percent reduction from baseline MADRS score 4 weeks after treatment which was found to be 52.5% in the SAINT group and 11.1% in the sham group. The remission rates in this study were 79% for the treatment group compared to 13.3% in the sham group. 

    These are significant results in the most difficult patient population to treat. It’s important to point out that these participants had 10 hours of contact with the treatment team per day and the number of participants in the study was small. Both are confounding factors, but using sham treatment helps because most participants were not able to tell if they received the treatment or sham. The one thing that was more common in the treatment group was headaches which may have altered them to which groups they were randomized into.

    The authors justified the low number of participants because they achieved a very large effect size with statistical significance without additional participants. What is currently missing from the research is a large randomized controlled trial conducted independently of the research group who designed the protocol (something to look out for in the future). 

    Mechanism of Action (MOA)

    One question you may have been thinking about is how does TMS work and what is the proposed mechanism of action for SAINT? 

    TMS is a noninvasive method of modulating specific areas of the brain by generating a magnetic field which induces neural cell membrane potentials to depolarize in the brain under the coil. Placing the coil in the correct location is critical and there is a 30% chance of missing that location when MRI is not used to map the exact location of the dorsal lateral prefrontal cortex. 

    SAINT is thought to alter brain connectivity and increase neuroplasticity in ways that traditional forms of TMS do not. The preliminary evidence suggests connectivity between the amygdala, insula, and medial frontal gyrus is altered in a meaningful way resulting in the improvement in depressive symptoms. Studies are underway to assess the MOA further. 

    How Does SAINT Differ From Other Forms of TMS? 

    First it differs in the time frame, it takes place only 5 days while most other forms of TMS take a full 6 weeks to complete. The treatments during those 5 days are intense, it requires 10 treatments per day while standard TMS is usually once per day. 

    The time for each treatment in the SAINT protocol is much shorter lasting approximately 10 minutes compared to the 20 to 45 minutes usually required. 

    There are three established types of TMS that differ in the time it takes to complete the treatment session. 

    -The first one on the market was the figure 8 coil which took 45 minutes to complete each session 

    -The H coils were invented by Brainsway and these sessions take 20 minutes 

    -Theta-burst stimulation: only take 3 minutes, and this is the one that the SAINT protocol uses 

    The next question is where to place the coil and how to place it. Traditionally the coil is moved around until the thumb twitches, this is the so-called thumb center, and we can look at the homunculus drawing and see how large the thumb center is. Traditionally we would measure 7 centimeters away from the thumb center and that should be the left dorsolateral prefrontal cortex. This method is not very accurate missing the mark approximately 30% of the time. To fix this problem the SAINT protocol uses MRI guided imaging to be sure the coil placement is accurate. You can also use EEG or PET scans to guide placement. 

    Conclusion

    -While I’m glad there is innovation in TMS treatment, and the results thus far have been impressive we have to keep in mind this machine is now being marketed by a startup company and has left the world of academia. 

    -It’s unclear if you need their machine to produce similar results as theta burst TMS already exists and MRI guided placement of the coil on the dorsal lateral prefrontal cortex exists as well. The company claims they have developed an algorithm for placing the coil that is unique and this claim will need to be investigated further once the machines are available. 

    -Another concern is most of the research has been published by the same group that designed the protocol and has not been reproduced in large RCTs independently. 

    -My final concern is regarding the application of this treatment for the average patient. It requires a full 5 days and 10 hours of treatment over the course of the 5 days. This may or may not be feasible for the average patient with treatment resistant depression. We haven’t even talked about what this intensive treatment will cost and if insurers will pay for it, another potential barrier. 

    -I would also like to see this go head-to-head in a study with Ketamine infusions and ECT. 

  • Can MDMA Cure Post Traumatic Stress Disorder (PTSD).

    Can MDMA Cure Post Traumatic Stress Disorder (PTSD).

    Introduction

    The entactogen MDMA overlaps with the chemical structure of methamphetamine and mescaline and has biological effects similar to epinephrine, dopamine, and serotonin. 

    It increases the release of monoamines through the reversal of transporter proteins and reuptake inhibition specifically serotonin and norepinephrine. Not only does it block reuptake of serotonin and norepinephrine it enhances the release as well and inhibits VMAT preventing the packaging of monoamines into vesicles making more available for release. It also modulates glucocorticoids through the HPA axis, decreases amygdala and hippocampal activity, increases oxytocin, and increase prefrontal cortex activity. 

    Medical Use

    MDMA started out as a therapeutic agent to enhance blood clotting for surgical procedures and trauma. Turns out it does not work very well for that indication, who would have thought. It’s currently listed as a schedule I substance (defined as having no accepted medical use, high abuse potential, and lack of accepted safety). 

    It was later discovered to have “empathogenic effects” helping individuals who use the medication to feel more connected to their fellow human beings. After all isn’t that what we are all after? A deep connection to others and people who truly understand us. The original name for the drug was empathy, but that has changed over the years to molly and escstcy. Personally, I like names that describe what a drug does, and empathy or empath is just so much more marketable don’t you think?

    Why PTSD is a Big Problem

    With several recent wars in both Iraq and Afghanistan, America has a PTSD problem with many combat veterans returning home and requiring treatment. If you ever treated patients with PTSD than you know it’s difficult and the therapy can be intense. Many patients are unable to sit with the discomfort required to reconsolidate these memories. Having worked at the VA for one year I was surprised by the number of vets with non-combat related PTSD. Honestly, they the vast majority of my cases were people who had accidents while working or in training and subsequently developed PTSD. 

    The idea is we need methods to enhance the efficacy and speed of trauma focused psychotherapies. What better way to do that than with empathy a medication that enhances feelings of connection. The basic idea being the patient would be given MDMA and then undergo psychotherapy and by using the medication it can influence fear extinction and memory reconsolidation. There are many mechanisms at play including effects on dopamine, serotonin, BDNF, cortisol, and oxytocin. 

    The concept of using a psychedelic drug to enhance the effects of psychotherapy is not a new concept, and was done for years using LSD and other compounds. What is different now, is we are trying to put the scientific rigor behind the studies to prove that it works better than placebo, and to learn more about the mechanism of action. 

    I want to point out that the main benefit of all these psychedelic medications seems to be enhanced neuroplasticity and the ability to form new connections in critical neurocircuits much easier than would otherwise be possible. 

    Benefits of MDMA Assisted Psychotherapy

    -Increase blood flow to the vmPFC decreasing activation of the amygdala largely responsible for the fear response 

    -Enhance the production of BDNF which improves the long-term potentiation and memory consolidation 

    -Elevate the stress hormone cortisol which interacts with glucocorticoid receptors in the hippocampus to improve memory 

    -Elevates the prosocial neuropeptide oxytocin which decreases activation of the amygdala and enhances connection with the therapist

    -Increased levels of dopamine which can destabilize the old memories and help with reconsolidation of new ones 

    -Increased serotonin levels resulting in prosocial and positive affective states. 

    The goal of PTSD treatment is to prevent the patient from being held hostage by these memories. We want to destabilize the old memories, modify them, and reconsolidate the new memories. The trauma still occurred, but the patient no longer has the same fear reaction to the traumatic memories. 

    MDMA-Assisted Therapy proved to be highly effective in individuals with severe PTSD. 

    -In this study investigators gave patients with PTSD 120-180 mg of MDMA along with a trauma focused psychotherapy. There were significant rates of both response and remission compared to placebo. 

    -MDMA was well tolerated 

    -It was granted breakthrough status by the FDA 

    -This was a big deal in the news and media outlets 

    -It needs to be replicated to confirm the results 

    Potential Adverse Effects of MDMA 

    -Potential for abuse and diversion (probably no take homes) 

    -Possible hyperthermia or hyponatremia (more common in the recreational use environment than clinical) 

    -People often engage in prolonged physical activity in hot environments and do not consume enough water this results in dehydration and possible hyperthermia (think large dance party)

    -In the opposite case the person overcompensates and overconsumes water diluting their blood and causing hyponatremia. Excess of anything can cause problems and water is no exception. 

    Blue Monday and Black Tuesday 

    -Use of MDMA can cause low mood, irritability, and fatigue. It can occur for days after recreational use. 

    -In the clinical setting, fatigue, anxiety, low mood, headaches, and nausea can occur in the week after treatment 

  • When Serotonin Goes Bad

    When Serotonin Goes Bad

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

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

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

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

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

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

    Key Features of Serotonin Syndrome: 

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

    What is Clonus: 

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

    Treatment: 

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

    The Most Feared Side Effect of antipsychotic Medication

    Introduction: 

    I get a lot of questions about the risks and side effects associated with antipsychotic medications. These medications are no longer used exclusively in schizophrenia, and they are now widely accepted as treatment for bipolar disorder, adjunctive therapy for depression, and even severe anxiety disorders resistant to other medications. 

    As a result, more people than ever are being prescribed these medications and many are concerned about the risk of side effects. One that I get asked about all the time and maybe the most feared of all side effects is the often-irreversible movement disorder called tardive dyskinesia (TD). 

    This discussion and video will help you understand the risk of developing TD and the approaches to managing it should symptoms develop. 

    EPS and Dopamine Blockade: 

    Dopamine receptor blockade can cause a variety of movement disorders, after all dopamine is directly involved in the process of movement. We call the movement disorders associated with dopamine blocking medication extrapyramidal syndromes (EPS). 

    Most EPS develop shortly after staring medication and are treatable with medication and stopping the offending agent. This is not the case for TD. There is a delay in the onset of symptoms (tardy) and persistence of the symptoms well after the medication has been stopped. 

    TD can develop after medication is used for a few months, or as little as a few weeks in the case of elderly patients. TD can also occur when a medication is discontinued or reduced. 

    Myths About TD: 

    • The longer you stay on an antipsychotic the more likely you are to develop TD. The prevalence (proportion of people who have a condition at or during a particular time) of TD increases with time, but the incidence (number of new cases) decreases with time. 
    • With first generation dopamine blockers 40-50% of patients developed TD but not in a linear fashion. Half of the patients developed TD within the first 5 years of taking medication. The incidence is about 5% per year over the first 5 years and then the incidence decreases to 1-2% per year and levels off after that. 
    • TD is more likely to occur in the first few years of treatment and less likely after 5 years of treatment. 
    • The risk of TD does not increase if acute EPS occurs and does not decrease if no acute acute EPS develops

    Risk factors for the development of TD: 

    • Diagnosis of schizophrenia 
    • Older age 
    • Female sex 

    Schizophrenia itself causes TD and has been described in the literature long before medications were used as treatment. The prevalence was lower about 5-10% Vs 40% seen after medications were used in treatment. This occurs because schizophrenia is not just a disease of the cortex it also involves the basal ganglia which is responsible for the movement disorders. 

    TD Risk at 1 Year of Treatment: 

    • Risperidone 0.6% 
    • Olanzapine 0.5% 
    • Haloperidol 2.7% to 4.5% 

    It’s clear from this data that first-generation dopamine blocking medications have a much higher rate of TD compared to the second-generation medications. This 0.5% rate is similar to the rate seen in the natural course of illness in schizophrenia (essentially the same as placebo). 

    In patients with mood illnesses who use dopamine blocking medications there are very low rates of TD. It can occur in mood disorders but it’s very infrequent and does not occur at nearly the same rates seen in schizophrenia.

    The risk of TD is associated with the underlying pathology of schizophrenia which is distinct from other mood disorders. 

    Treatment of TD:

    For a long time, there was no treatment for TD. In the last few years two medications have been developed Valbenazine (ingrezza) and deutetrabenazine (Austedo) both of which are FDA approved. 

    The mechanism of action of these two medications is VMAT-2 inhibition. Vesicular monoamine transporter 2 inhibition results in decreased monoamine activity at the synapse. 

    The studies used to gain FDA approval of these medications showed a mild improvement on the abnormal involuntary movement scale of 2-3 points in patients with mild TD. 

    It’s important to keep in mind TD did not go away fully but it did improve over placebo. 

    The best treatment for TD is to stop the dopamine blocker. In some cases, if the dopamine blocker is stopped early enough TD is reversible. In many cases the medications are continued because there are no other clinical options and you are left with treating TD with VMAT-2 inhibitors.