Category: Psychiatry

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. 

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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. 

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Is ADHD A Real Psychiatric Disorder: This Will Blow Your Mind 

Introduction 

Attention deficit hyperactivity disorder (ADHD) in the adult population is a topic of great debate. There are many psychiatrists who say ADHD symptoms do not suddenly disappear as a person continues into adulthood. On the other hand, there are some psychiatrists who do not think ADHD is a real diagnosis. 

The term ADHD might be better thought of as attention deficit disorder (ADD). The concept of hyperactivity is more common in the child/adolescent patient population. It’s unclear if the hyperactivity is related to executive dysfunction which is the hallmark of ADHD. It may be that the hyperactivity is within the range of normal (agitation or activation) for a child, or signs of another mood disorder such as mania in bipolar illness (especially true in the adult population as bipolar diagnosis is commonly reserved for adult patients). 

We can make an argument that placing children in a traditional school setting where they are asked to sit and pay attention to uninteresting material for 7 hours is unnatural and directly against the way humans evolved to function. The human body and mind evolved to move and be active not to sit in classrooms. As a result, agitation, hyperactivity, and acting out can be the result of this unnatural state. 

The hallmark of ADHD is attentional impairment and executive dysfunction. Hyperactivity is not seen in adult populations with ADD. 

Attention As a Trait 

Attention can be thought of in the same manner as blood pressure. There is a mean blood pressure in the population but there will be individuals that fall outside the standard curve. Most people in the population will fall in the middle having a reasonable amount of attention and those with low attention levels do not necessarily have a disease although they may have consequences associated with reduced attentional activity. When someone is overly attentive it can be a symptom of disorders like obsessive compulsive disorder (OCD) or psychosis. Like blood pressure, having readings that are too high or too low can cause problems. It’s normal to have a certain amount of inattention, and we can think of attention as a spectrum with a range of normal levels. 

What are the Causes of Inattention 

-It could be a perfectly normal trait, as we explained some people have lower attention spans naturally as a personality trait 

-Mood disorders like depression and bipolar disorder have in inattention as a possible consequence of the change in mood 

-Psychotic disorders also have cognitive changes that may cause inattention (internal preoccupation) 

-Anxiety disorders 

-Neurocognitive disorders 

-We should avoid diagnosing ADD in the setting of one of these other conditions. 

Would you diagnosis ADD during a manic episode?

Prevalence of ADHD in the U.S. 

-The prevalence of ADHD in the U.S. ranges from 5.6% to 15.9% and there is great variability depending on the geographic region 

-For most biological diseases we should see similar prevalence rates across populations and geographic regions. For example, schizophrenia has a prevalence of about 1% worldwide. So why do we see significant differences across the U.S.? 

-We do not know much about the role socioeconomic factors, diet, exercise, and other social factors play in the development of ADHD. It’s possible that these are significant contributing factors resulting in the symptoms associated with ADHD. 

Is ADHD a neurodevelopmental issue? 

-One way of thinking about ADHD is as a neurodevelopmental problem that eventually improves over time. 

-In children with ADHD they seem to achieve peak cortical thickness later than children without ADHD, this has been confirmed on imaging studies. 

-The important part is eventually these children catch up with the normal controls. It’s more a delay in brain development and not a permanent state. 

-The ADHD children are about 2 years behind the normal controls and the area of greatest delay is the prefrontal cortex which is responsible for executive function. 

How Common is ADHD and Does it Last into Adulthood? 

Over the past decade ADHD in adult populations has gotten more attention. Some would say the prevalence in adults is 4% to 5% with equal rates being seen in men and women. 

The national comorbidity survey estimated 46% of children with ADHD have symptoms that persist into adulthood. Many of these individuals had comorbid anxiety disorders and we know anxiety can be a major cause of inattention and executive dysfunction. 

In other studies, similar findings were reported. What stands out to me in all these studies is the high rates of comorbid mood disorders including depression and bipolar disorder. It’s hard to make a diagnosis of adult ADHD in the presence of other conditions considering the significant overlap of symptoms and cognitive dysfunction associated with mood disorders. 

It’s possible that mood and anxiety disorder can account for most adult ADHD cases and a variation of a normal trait could explain the rest (individuals with low attention) 

Looking at medication response doesn’t help us much as amphetamines are helpful in everyone even those who do not have a psychiatric disorder (think college kids taking them for midterms) 

When you correct for comorbidities in Adult ADHD, only about half of the young adults meeting criteria for ADHD had ADHD only. Estimates from this showed that most children diagnosed with ADHD were no longer meeting criteria in adulthood (83% no longer had symptoms). Many of the newly diagnosed cases of ADHD were in individuals who did not have ADHD as children (87% did not have ADHD as children).  

This indicates that about 20% of children diagnosed with ADHD will have symptoms persist into adulthood, the other 80% will not 

In animal models, amphetamines have been shown to have some dangerous effects 

-Decrease response to reward stimuli 

-increased anxiety 

-decreased dopamine activity 

-decreased long-term survival of neuronal cell in the hippocampus (excitotoxicity) 

Risk of Substance Use With Stimulant Prescriptions

Most psychiatrists will tell you the risk of substance use disorder does not increase with stimulant medication treatment; in fact it’s reduced when ADHD is treated. However, a well-designed randomized controlled trial of delinquent behavior and emerging substance use in medication treated children found significantly higher rates of substance use in the stimulant treated individuals. The conclusion by Molina et al. was we need to re-evaluate the risk of substance use disorder as children age when they are prescribed stimulants. Now correlation does not equal causation, but this should give us some pause when blinding stating there is no risk for addiction with stimulant use (this claim is mostly based off observational data and not randomized controlled trial data). 

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Gabapentin/Neurontin The Most Common off-Label Prescription in Psychiatry 

Introduction 

Gabapentin is approved by the FDA for three specific indications to prevent and control partial seizures, relieve nerve pain following shingles (post herpetic neuralgia), and to treat moderate to severe restless leg syndrome. Unfortunately, less than 1% of the prescriptions written for gabapentin are for the above listed FDA approvals. In fact, much of the off-label prescribing of gabapentin is done for the treatment of psychiatric and substance use disorders. 

We were first alerted to the misleading marketing practices when Pfizer paid a $2.3 billion dollar fine for misleading clinicians through their marketing campaigns. Gabapentin is often thought of as a benign medication that can address symptoms in several common disorders including migraine, chronic pain, fibromyalgia, opioid use disorder, anxiety, and mood disorders. There is now mounting evidence that this medication is not as safe as people once assumed yet many of these prescribing practices continue despite a lack of quality data. Today we will review the safety and efficacy of gabapentin in psychiatric disorders. 

How Does Gabapentin Work?

Gabapentin functions by binding to the alpha-2-delta subunit of voltage gated calcium channels theoretically offering antipain, anticonvulsant, and anxiolytic properties. Although it’s structurally related to the GABA neurotransmitter, there is no direct interaction at GABA A or B receptors. 

Why is there such an increase in Gabapentin prescribing?

In the United States the opioid epidemic drove much of the 64% increase in gabapentin prescriptions 2012 to 2016 as policy makers searched for safer alternatives for pain management. Although lacking any data for the treatment of chronic pain, gabapentin was elevated into this role because of several factors cost, non-controlled status at the federal level, evidence in neuropathic pain, and benign side effect profile. 

However, the risk for gabapentin abuse became apparent as more prescriptions were written. The risk of adverse effects was prevalent when combined with other CNS depressants such as opioids, the exact thing gabapentin set out replace. Approximately 15%-22% of people with an existing substance use disorder abuse gabapentin. Those who overused gabapentin were found to be at increased risk of all-cause or drug-related hospital stay and emergency visits for altered mental status and respiratory depression. 

The off-label prescribing of gabapentin comes with risk. 

Evidence For Use in Anxiety Disorders

The evidence for gabapentin’s use in anxiety disorders comes from only two industry sponsored studies with a total of 172 participants. These are relatively small but well-designed studies that provide limited evidence for the use of gabapentin in anxiety disorders. The first study was in 1999 and looked at the use of gabapentin in social anxiety disorder. 69 participants were randomized to placebo or gabapentin 900-3600 mg/day for 14 weeks. A significant reduction in social anxiety was observed over the 14 weeks and the conclusion was more studies were needed to confirm the results. The other study looked at panic disorder with the same study design and doses of gabapentin, only this time the study lasted 8 weeks. The results indicated gabapentin was effective for severe panic disorder. One thing we notice is neither of these studies focused on generalized anxiety disorder. These results have not been replicated in other studies. 

There is far more evidence for the use of pregabalin in anxiety disorders. In Europe it does have regulatory approval for generalized anxiety disorder. 

Evidence For Use in Bipolar Disorder 

I’m going to burst this bubble and maybe a few other bubbles up front. While some believe all anticonvulsants are “mood stabilizers” they are wrong. Gabapentin has never proven in RCTs to treat mania or any other aspect of bipolar disorder. Likewise, Topiramate and oxcarbazepine have performed poorly in studies assessing their efficacy in bipolar disorder. Simply put, if you are on any of the three medications as primary mood stabilizers it’s best to consider other options such as lithium. 

Evidence For Use In Alcohol and Cannabis Use Disorder  

While addiction treatment is part of the reason we are in this mess with gabapentin, it does have a role in alcohol use disorder (AUD) and cannabis use disorder. The APA added gabapentin as a second line option for AUD because patients who take it for this indication report fewer heavy drinking days with an effect size in the moderate range. There is also some indication that sleep quality improves with gabapentin when patients are cutting back or stopping alcohol use. Alcohol is known to worsen sleep with more frequent nighttime awakenings. The dose range is 300-3600 mg/day in divided doses with many using an average of 900 mg/day. 

Gabapentin is sometimes used for alcohol withdrawal in place of benzodiazepines or phenobarbital. There were a few seizures in the gabapentin groups raising some questions about its use in severe alcohol withdrawal. It’s probably best left for those with less severe dependence. 

Typical Taper for Alcohol Withdrawal

-Start with 1200-2400 mg/day in three divided doses 

-Taper to 600 mg/day over the course or 4-7 days watching for objective signs of alcohol withdrawal and have Ativan available should a seizure develop. 

-Taper by 300 mg/day over the next 2-3 days until the medication is completely off. 

In cannabis use disorder there is limitted data. A single study showed improvement in withdrawal symptoms, reduced cannabis use, and improved executive function but this is not enough to recommend gabapentin on a regular basis in clinical practice. 

It’s important to note gabapentin failed in controlled trials for cocaine, methamphetamine, benzodiazepine, and opioid use disorder. It’s dangerous to combine gabapentin and opioids as discussed earlier in the video. 

A Quick Note on Gabapentin for Chronic back pain 

There are 8 total studies including a systematic review and meta-analysis to assess pain relief in patients with chronic lower back pain a reason many patients tell me they are taking gabapentin for. When you pool this data together, gabapentin demonstrated minimal improvement in pain compared to placebo and had an increase in adverse effects including dizziness, fatigue, and visual disturbances.

Adverse Effects 

The most common side effects include sedation, fatigue, dizziness, imbalance, tremor, and visual changes. 

Dosing

Gabapentin has a short half-life of 6 hours and will need to be dosed three times per day. The kinetics of gabapentin are not linear which means levels in the blood do not rise consistently. For a 900 mg dose, only 540 mg is absorbed. This has to do with the transporters responsible for gabapentin absorption becoming over saturated limiting the amount of medication absorbed. 

Conclusion

While there are very good reasons to consider the use of gabapentin many of the common reasons cited in clinical practice lack the appropriate evidence to support using the medication. It’s best to stick with FDA approved indications and if you are prescribing it off-label consider only using it for the disorders with the most evidence in my opinion that is alcohol use disorder when other treatments have failed. 

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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 

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How to Change Your Mind: The Current State of Psychiatry and Psychedelics

There is no hotter topic in the world of psychiatry than the reemergence of psychedelics as therapeutic tools for the treatment of mental illness. When esketamine was approved by the FDA in March of 2019 it opened the doors for medications like MDMA, psilocybin, and mescaline as possible therapeutic agents. 

I’m excited about these new options for therapy but I also want to make sure the science backs up the personal experiences of individuals who use these medicines in uncontrolled settings. 

Introduction:

The psychedelic era was a time of social, musical, and artistic change influenced by the use of psychedelic drugs that occurred between the mid-1960s and mid-1970s. Although this era lasted for some time it largely fell out of favor for legal reasons and wasn’t a topic in modern psychiatric training until just recently. It seems like overnight there are New York times articles, Netflix documentaries, and evening news coverage about psychedelics.

What’s the story are we ready to prescribe everyone psilocybin and MDMA as a form of mental health treatment? 

History of Hallucinogens in Medicine

For over 5 millennia humans have been attempting to alter their state of consciousness. Some have argued it goes even further back to primate ancestors who consumed large quantities of ripe fermented fruit to alter their state of consciousness (drunken monkey hypothesis). I’m not sure how correct this theory is but it’s safe to say psychedelics have been around for a long time. 

In 1943 Albert Hofmann a chemist by training, invented LSD by accident. He started the research in 1938 and announced that he sampled the chemical in 1943. Not only did he synthesize it, but he was getting high on his own supply. In 1957 this same chemist isolated psilocybin from the hallucinogenic mushrooms.

In the 1940’s LSD was marketed as a drug to assist psychotherapy, the so-called drug assisted psychotherapy which is making a comeback today. Unfortunately, of the 1000 studies published looking at psychedelics as a model for psychosis and as therapy were small and uncontrolled. 

In the 1970’s most of these medicines were placed into schedule I status making it exceedingly difficult to study the medicines further for therapeutic effects in a controlled setting. A Randomized controlled trial is considered by many to be the highest standard of scientific evidence. 

Classes of Hallucinogens 

For years people thought of psychedelics as LSD or psilocybin, the term now includes other medicines. The term psychedelic is derived from two Greek words meaning mind manifesting. Essentially psychedelic and hallucinogen are being used interchangeably these days but do have separate meanings.

Classic Hallucinogens 

-Tryptamines: psilocybin, LSD, and DMT 

-Phenethylamines: Mescaline 

Non-Classic Hallucinogens 

-3,4-methylenedioxymethamphetamine (MDMA)

-Dissociative Anesthetics: Ketamine, PCP, Dextromethorphan 

Therapeutic Targets for Psychedelic Use

Disorders Under Investigation: 

-Depression 

-Anxiety

-PTSD

-OCD

-Cancer related stress and psychological issues 

-Addiction 

-Smoking cessation 

-Sexual dysfunction 

-headaches 

-inflammatory disorders 

Maybe the best studied area is in end of life and palliative care settings. 

Mechanism of Action

-The primary mechanism of action is 5-HT2A receptor stimulation 

-5-HT2A is the most abundant serotonin receptor in the central nervous system and cortex of the brain. 

-Stimulating the 5-HT2A receptors will increase the release of glutamate in the cortex 

-Stimulation of 5-HT2A receptors in the visual cortex can lead to visual hallucinations. Stimulation in the ventral tegmental area can produce a situation like that of schizophrenia with delusions and hallucinations. 

-Most atypical antipsychotics bind to and block 5-HT2A receptors and would mitigate the effects of psychedelics 

Neurobiology

People often make comments like we don’t know how much serotonin is enough, then conclude that medications do work or the therapies we are using are invalid. That’s because they are thinking about mental illness and these medications too simply. Most psychiatrists do not believe in or talk about the chemical imbalance theory of treating mental illness. We think about mental illness and problems with neural circuits, nodes, and networks. What medications including the psychedelics achieve is an alteration in the connectivity of these networks and the ability to form new connections. 

We have a default mode network which is famously active when a person is not focused on the outside world and the brain is just daydreaming. What psychedelics do is decrease brain connectivity in this default mode network followed by the establishment of new connections. 

Hypothetically this rewiring of the brain allows for the replacement of faulty connections resulting in mental illness and the formation of new healthy connections through psychotherapy provided during treatment. This may be why the antidepressant effects last far beyond other interventions with less frequent dosing. 

There are identifiable changes in network connectivity that coincide with subjective improvement. 

The Mystical Experience: Is Tripping Required for a Therapeutic Effect

-There is a mystical experience questionnaire that has been validated and used in these studies. It seems that the more profound the mystical experience the better the treatment effect subjectively 

-While the spiritual experience many individuals have while taking these medicines is profound and meaningful to the individual, we are not sure that having a “trip” is required to produce a therapeutic effect. 

Side Effects of Psychedelic Use 

While some may claim there are no adverse effects from plant-based medicine that is not true. 

Things like increased blood pressure, berating rate, and body temperature have been reported. 

-Loss of appetite, dry mouth, sleep disturbance, uncoordinated movements, panic, paranoia, psychosis, and bizarre behaviors 

Long-Term Effects: 

Persistent Psychosis: A series of continuing mental problems including 

-visual disturbances

-disorganized thinking

-paranoia

-mood changes 

Hallucinogen Persisting Perception Disorder (HPPD) 

-Recurrences of certain drug experiences such as hallucinations or visual disturbances 

-These experiences often happen without warning and may occur within days of last use or even years after taking the drug 

-These experiences can be mistaken for neurological disorders such as strokes or brain tumors. 

Conclusion

At this time what we can say about the current state of psychedelics in psychiatry is they are under investigation. We do not know yet if they are safe and effective for treatment of mental illness on a mass scale. We have some encouraging evidence but there is an absence of large randomized controlled trials proving efficacy and safety. Psychedelics are not ready for clinical practice and should not be recommended as a treatment for mental illness until the proper studies have been conducted. 

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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 
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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. 

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The Best Antipsychotic Medication in The World 

Introduction:

I’ve said it before in previous videos, older medications are more effective and newer medications have fewer side effects. 

The advent of SSRIs in the late 1980’s and early 1990’s was largely driven by safety and not efficacy. The same is true for antipsychotic medications. This may be the reason most people haven’t even heard about Clozapine (brand name Clozaril). 

Efficacy

Clozapine is the single most effective antipsychotic available, and it works in treatment resistant schizophrenia where no other medication is proven to be effective. 

The results speak for themselves, 30% of previously treatment resistant patients experience symptom reduction within 6 weeks and that number jumps to 60% after 6 months of treatment. 

Clozapine has a slew of additional benefits including mood stabilizing prosperities (it can be used in bipolar disorder), reduction in psychogenic polydipsia and the hyponatremia associated with it, reduction in hostility and aggression, reduction in the risk of suicidal ideation, improvement in substance use, and it may even help patients quit smoking a difficult task in schizophrenia. 

So why are most schizophrenic patients not on this medication if it’s so great? 

Side effects, side effect, side effects

-Sedation: feeling tired this can largely be mitigated by dosing the medication at night before bedtime. 

-Tachycardia: It’s worth getting an EKG in patients with preexisting heart conditions or those at high risk due to hypertension and hyperlipidemia 

-Sialorrhea: excessive saliva production leading to drooling, no one wants this 

-Dizziness

-Constipation: this should be addressed immediately if a patient complains about it as it can lead to serious complications. In many cases Senna and Colace will do the trick

-Orthostatic hypotension 

-Weight gain 

Serious and potentially fatal Side effects include: 

-Agranulocytosis: decreased absolute neutrophil count which can result in increased risk for serious infection and the reason everyone on the medication gets weekly blood draws for the first 6 months 

-Seizures: clozapine is known to lower the seizure threshold 

-Myocarditis: inflammation of the heart usually due to a viral infection 

The risk for agranulocytosis is highest when starting treatment, usually during the first year of treatment (0.8%) and the maximum risk is between 4 and 18 weeks (when 77% of cases occur), although it can still occur at any point in the treatment.

Agranulocytosis

Monitoring is thus very important, and each patient must be registered in the Risk Evaluation and Mitigation strategy (REMS) data base before starting the medication. 

A CBC with differential must be drawn to calculate the absolute neutrophil count prior to starting treatment and then weekly for the first 6 months. Then monitoring continues every 2 weeks for the next 6 months and finally monthly after the first year of treatment. 

If agranulocytosis occurs stopping clozapine allows majority of cases to recover within 14 days. 

Now that we know that this medication is very effective but comes with a high side effect burden a natural next question might be why does the medication work? 

Mechanism of Action

Clozapine has very low affinity for the D2 receptors which is unique as most other antipsychotics will bind strongly to D2 receptors. Clozapine had far greater D1 and D4 binding affinity, blocking both receptors. 

Clozapine also has significant activity at other neurotransmitter sites. It blocks alpha receptors which may be the reason for orthostatic hypotension. It blocks histamine H1 receptors resulting in sedation and weight gain. It blocks 5-HT2A serotonin receptors and is highly anticholinergic resulting in constipation and urinary retention. 

It has two unique properties; it influences the glutamate system by altering NMDA receptor sensitivity and increases the release of brain derived neurotrophic factor BDNF. 

Metabolism And Drug Interactions

Clozapine is primarily metabolized by CYP450 1A2 and 3A4 and cigarette smoking will cause a reduction in clozapine levels due to induction of CYP 1A2. 

Before Starting the Medication

Before starting clozapine, the ANC must be above 1,500. If neutropenia develops treatment will depend on the severity of the drop. 

Mild Neutropenia: ANC 1,000-1,499, you would continue treatment and check an ANC three times weekly until it reaches 1,500. 

Moderate Neutropenia: ANC between 500 and 999, stop treatment and check the ANC daily until it reaches 1,000 then 3 times weekly until it reaches 1,500 then weekly for 4 weeks before returning to the patients prior monitoring schedule. 

Severe Neutropenia: ANC less than 500, stop treatment and check an ANC daily until it’s 1,000 then 3 times weekly until it’s 1,500. The patient should not be rechallenged without a hematology consult and clear benefits that outweigh the risks. 

Dosing

Clozapine can be started at 12.5 to 25 mg at bedtime. The dose can be increased 25 mg/day inpatient and 25 mg per week in the outpatient setting as tolerated. 

You can overlap prior treatment with another antipsychotic and tapper the old medication once clozapine dose reaches 100 mg or more. 

Plasma Levels

Clozapine dose should be based on serum levels, with a target blood level of 200 to 300 ng/ml. If there are still symptoms present the target serum level is 450 ng/ml. There are no benefits to serum levels above 900 ng/ml. 

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The Neurobiology of Appetite

Metabolic set point 

People alter the quantity and frequency of food consumption daily and yet the brain seems to have a regulatory process that allows people to maintain a relatively stable body weight. 

Isn’t that crazy? 

Anyone who has ever tried to diet knows all too well about this metabolic set point. There are staggeringly low rates of success with diet programs. A systematic review of studies published between 1931 and 1999 found that only 15% of patients achieved dietary success after 5 years. Most people who diet will slowly return to their preexisting weight within 1 year.

This metabolic set point appears to be controlled by our genetics. There is a strong correlation between the body mass of biological parents and adoptees in adoption-based studies. In the case of weight, genetics has far more influence than environmental factors. 

Despite all this obesity rates in the United States as well as other developed countries continues to rise, so what gives? 

Our genes have difficulty responding to the modern environment. 3000 years ago, when food sources were scarce, it was advantageous to consume and store as many calories as possible. However, in the modern world where there is no shortage of opportunity to consume calorie dense foods, our genetics are working against us. The weight issue is genetic but also influenced by availability of high-calorie delicious food. 

When it comes to weight, energy in (food) must equal energy out (heat and work). The energy out is made up of the resting metabolic rate (calories burned when the body is stationary) and physical activity. The brain has a unique mechanism for managing the RMR. When more calories are consumed the RMR increases and when we diet the RMR is turned down. 

To solidify the point, we can look no further than The Biggest Loser competition. Investigators assessed 14 of the 16 contestants before the competition, after completion of the 30-week program, and 6 years after the show. 13 of the 14 study participants regained weight and 4 were heavier than when they started the competition 6 years ago. The real downer was they all burned less calories at rest 6 years after the show ended. Despite exercising more and theoretically being much healthier their RMR decreased. 

What are the important signals used by the body that indicate when to eat and when to stop eating?

Short-Term signels include: 

Glucose: This is the primary nutrient that mediates satiety. Hypoglycemia will stimulate hunger and increase eating, while glucose infusions will decrease food intake. 

Mechanoreceptors in the gut: The physical presence of food in the stomach activates these receptors due to stretching, the vagus nerve transmits signals of gastric stretch to the hindbrain to decrease eating. 

Gut Hormones: The most well understood is cholecystokinin (CCK) which is released by endocrine cells in the small intestine. This will inhibit further food intake by stimulating the vagus nerve and decreasing gastric emptying. People have tried using CCK as a weight loss measure but all it does is decrease the size of meals but increases the frequency of eating thus producing a net zero effect on weight loss.

Ghrelin is the only gut hormone that stimulates hunger. Some suggest that decreased ghrelin produced by the stomach is the reason gastric bypass surgery is effective for weight loss. 

It’s now known that adipose tissue releases a hormone that conveys information about energy stores. Leptin is produced by fat cells and increases or decreases based on the total amount of fat. Leptin is a hormone that tells the body to stop eating. In the case of obesity leptin levels are high and energy expenditure increases while food intake decreases. When someone goes on a diet and fat stores decrease leptin decreases resulting in decreased energy expenditure and increased food intake. 

Two groups of neurons in the arcuate nucleus of the hypothalamus mediate the leptin signal, proopiomelanocortin (POMC) and neuropeptide Y (NPY). POMC stops eating and NPY increases food intake and decreases energy expenditure. In obesity there is increased leptin which inhibits NPY and activates POMC resulting in increased energy expenditure and decreased food intake. The opposite is true for the lean individual. 

Eating and Pleasure

It’s well established that eating can result in pleasure, we have all had this experience after a stressful week a good meal can instantly change our mindset. The pleasure from food is likely an adaptation that enhanced survival when food sources were scarce. Increased dopamine in the nucleus accumbens and release of endogenous opioids appears to be more active when we are eating a meal we enjoy. 

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