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 

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. 

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

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. 

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. 

 

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. 

Omega-3 Fatty Acids and Mental Health

Omega-3 fatty acids are reported to help with several physical and mental health conditions. 

They are termed essential because they cannot be produced by the body and must come from the diet. 

In fact, I use 1000 mg of omega-3 fish oil daily as part of my own supplement routine.

How Do Omega-3s Work:

Omega-3’s coat neurons, increase cell membrane fluidity, have neuroprotective properties, and the most well-established mechanism is an anti-inflammatory action. They directly affect arachidonic acid metabolism because they displace arachidonic acid from membranes and compete with it for the enzyme that catalyzes the biosynthesis of thromboxanes, prostaglandins, and leukotrienes involved in the inflammatory process thus reducing the formation of these products. 

Indications For Omega-3 Use In Psychiatry:

In mental health the most well-established use of Omega-3s is for the treatment of depression. It’s been looked at as a primary treatment as well as augmentation. The results aren’t that great when Omega-3s are used as stand-alone therapy. As augmentation they have an effect size of 0.5 to 0.6.

Given our previous talks about inflammation and depression, people with high inflammatory biomarkers may respond better to Omega-3 treatment. 

Omega-3s And Schizophrenia:

Maybe the most interesting data comes from studies of Omega-3 use in schizophrenia. It seems to work best when started early in the illness when the first signs or symptoms appear. There also seems to be a reduction in white matter changes on imaging studies. 

This raised the important question; can we prevent schizophrenia? 

Vienna Study:

There was a study published in nature communications that looked at outcomes in the prevention of psychotic disorders in Vienna. 

They started with 12-week trial with omega-3s which proved to reduce the risk of progression to a psychotic disorder in young people with subthreshold psychotic states for a 12-month period compared to placebo. 

They then completed a long term follow up of the study to show that brief intervention with Omega-3s reduced the risk of progression to a psychotic disorder and psychiatric morbidity. 

A year after the Omega-3 treatment only 5% converted to schizophrenia, compared to 28% in the control arm. Seven years later the rates of conversion to schizophrenia were 10% Vs 40% with most of the patients being retained in the study. 

Side Effects of Using Omega-3:

There are very few risks to adding omega-3 fatty acids to existing psychiatric treatments. Fish burps are a common occurrence and can be mitigated with enteric coated capsules or refrigerating the capsules. Omega-3 can increase bleeding time and require careful monitoring if the person is scheduled for surgery or taking anticoagulants. Keeping doses at 1000 mg/day is advised for this population. 

Sources of Omega-3:

You can use a supplement, or you can consume fish like salmon, herring, or anchovies two times per week to get an adequate dose. 

Ensuring the EPA to DHA ratio is 2:1 (EPA: DHA) or pure EPA is essential when selecting a product. Consumerlabs.com to help ensure the purity and potency of the product is accurate. 

The cost of adding an Omega-3 supplement to your treatment is $8 to $30 per month depending on the specific product. 

There is very little downside to increasing your consumption of Omega-3 fatty acids either from whole food sources or as a high-quality supplement. 

Hey Doc, What’s Psychogenic Polydipsia?

This is one of the interesting occurrences that can present on the medical floors, emergency rooms, or inpatient units. 

A patient comes in with an established diagnosis of schizophrenia and is currently taking ziprasidone. The person is constantly asking for glasses of water and drinking water excessively throughout the day. 

You might be thinking what is the harm in drinking water, isn’t staying hydrated a healthy behavior? 

…But you order a basic metabolic panel and find the persons sodium is 125 mEq/L. 

Now the panic sets in, it’s time to worry and the patient continues to complain of feeling thirsty and is noted to be urinating frequently. 

There are a few possibilities for the persons behavior, but we need to consider psychogenic polydipsia or primary polydipsia. This was first described in the 1930s in patients with schizophrenia who drank water excessively resulting in low serum sodium levels. 

The cause is unknown, but these patients may have an acquired defect in the hypothalamic thirst regulation. Medications have also been associated with worsening of psychogenic polydipsia. It’s thought to be related to the anticholinergic effects of many of these medications. Examples include carbamazepine, chlorpromazine, oxcarbazepine, haloperidol, and valproate. 

Psychogenic polydipsia (PP) is common, and it’s usually associated with schizophrenia but can occur in other psychotic, mood, and anxiety disorders. Some users of MDMA also develop PP. 

PP is a primary problem where the patient is drinking too much water. This results in a dilution of the blood and thus a low sodium level (defined as < 135 mEq/L) and low serum osmolality. The urine will also be dilute < 100 mOsmol/kg with low urine sodium. 

Two other potential places where we can see polyuria are in cases of hyperglycemia from uncontrolled diabetes and nephrogenic diabetes insipidus. The key distinction in the first case is hyperglycemia. The water is drawn out by osmotic diuresis secondary to excess glucose in the urine. The key labs here are a fasting glucose and a urine analysis which should show hyperglycemia and glucose in the urine. In nephrogenic diabetes insipidus the brain secretes ADH just fine, but the kidney does not respond to it. The urine will be dilute, but the serum sodium level will be high not low separating it from psychogenic polydipsia.

Treatment includes fluid restriction to 1000-1500 mL/day, this can be difficult to enforce even on an inpatient unit. The person may need to be watched because sources like the bathroom sink or even toilet may be used to consume more water. This is usually enough of a treatment, but should the sodium remain low you can add sodium chloride tablets 1-3 grams daily. 

In severe cases where the sodium drops below 120 the person can have a seizure. In these cases, it’s best to handle the fluid replenishment on the medical floor with 3% saline. 

You must be careful not to correct the sodium too rapidly as it can result in the dreaded central pontine myelinolysis which can result in quadriparesis. That’s why we correct the sodium at a rate of no more than 10 mmol/L/24 h or 0.5 mEQ/L/h 

Everything You Need to Know About Trintellix (Vortioxetine)

Introduction:

Vortioxetine is sold under the brand name Trintellix, and Brintellix and it’s approved for use in major depressive disorder. The name was changed to Trintellix in the U.S. due to confusion with Brillinta an anti-platelet medication. It was studied in generalized anxiety disorder (GAD) at lower doses, but the quality of the evidence is poor and does not appear to improve symptoms or quality of life in patients with GAD. 

I want to make a quick point before going into the details about the medication. When I say the effect size is moderate and Vortioxetine does not perform better than other options for depression, I’m not saying in an individual case that it may not outperform other antidepressants that the person has tried in the past. It very well might for that individual. I’m talking about on average in large sample sizes, Vortioxetine does not outperform other medications according to the current literature. It’s also not a go to medication for treatment resistant depression, the literature does not support this either.

The one place Vortioxetine does seem to stand out is cognitive function. Multiple studies have shown this medication to improve cognitive dysfunction associated with depression. It also appears to improve cognitive function in geriatric depression but failed to show any benefit in neurocognitive disorders like Alzheimer’s disease. It was also looked at as a potential treatment for attention deficit hyperactivity disorder (ADHD) but failed to show an adequate benefit in trials. 

Mechanism of Action and Receptor Targets

This medication falls into a class known as serotonin modulators and stimulators. It is thought to work by several different mechanisms:

-Serotonin reuptake inhibitor

-5-HT1A agonist (may diminish sexual side effects) 

-5-HT1B partial agonist 

-5-HT1D, 5-HT3 (may enhance noradrenergic and cholinergic activity that improves cognition while reducing nausea), and 5-HT7 antagonist (pro-cognitive and antidepressant effects) 

The most robust action is on serotonin reuptake and 5-HT3 antagonism, while the other interactions are considered minor. 

Target Affinity Ki (nM)Action 
SERT1.6Inhibition 
NET113Inhibition 
5-HT1A 15Agonist 
5-HT1B33Partial agonist 
5-HT1D 54Antagonist 
5-HT2C180 
5-HT3A3.7Antagonist 
5-HT719Antagonist 

Metabolism

Vortioxetine is metabolized by CYP2D6, 3A4/5, 2C19, 2C9, 2A6, 2C8 and 2B6, the half-life is 66 hours and it’s dosed one time per day. Reduction is dosing may be needed for patients taking strong CYP2D6 inhibitors (e.g. bupropion).

Dosing:

-5-20 mg/day 

-Tablets come as 5 mg, 10 mg, and 20 mg 

-The initial dose for depression is 10 mg which can be increased as needed to a maximum dose of 20 mg daily. 

-For GAD does were kept lower 5-10 mg/day range 

-Can be taken with or without food 

-It can be stopped without a tapper 

Side Effect:

Common side effects include nausea, vomiting, constipation, sexual dysfunction, weight gain is unusual but possible. Nausea and sexual dysfunction were the most common side effects; all other side effects were reported in less than 10% of cases. 

Sexual dysfunction was found in both the plebe group and the treatment arm. The incidence was 14-20% for placebo and 16-34% for those in the treatment arm.

Rare life-threatening side effects include seizures, induction of mania and suicidal ideation. 

Avoid using tramadol as it can increase the risk of seizure, and do not combine with MAOIs as this can result in serotonin syndrome. 

It’s generally not recommended in pregnancy. 

Conclusion

While this medication may be helpful for some individuals there is no evidence to support its use in treatment resistant depression or other disorders outside of the primary indication major depressive disorder. There does seem to be a benefit for patients who have significant cognitive dysfunction as a result of depression and maybe that is where this medication best fits into a treatment plan. The main side effects are nausea and sexual dysfunction which are common with all antidepressant options. You must also consider the cost of the medication in comparison to duloxetine which outperformed Vortioxetine in some clinical trials.

 

Major Depressive Disorder (MDD) With Psychotic Features

This is a diagnosis that I often receive questions about. It can be confusing, how do we know if the person has schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features? 

They all have psychotic symptoms such as delusions and hallucinations.

In this video I’m going to explain how we navigate this diagnostic dilemma. 

For one to be diagnosed with MDD with psychotic features they must meet criteria for major depressive disorder based on the DSM-5TR. 

As a reminder, to meet criteria the person must have 5 out of 9 symptoms within a two-week period and at least one symptom must be either depressed mood or loss of interest

In medical school they teach you the mnemonic SIGECAPS, an interesting fact is this is written the way you would fill out a paper prescription for depression. SIG Energy Capsules which you would give to a person with major depression because of the low energy and loss of interest commonly seen in major depression. 

Anyway…

The other criteria include 

-Weight loss or weight gain 

-Insomnia or hypersomnia 

-Psychomotor agitation or retardation 

-Fatigue or loss of energy 

-Feelings of worthlessness or guilt 

-Poor concentration 

-Recurrent thoughts of death or suicidal ideation 

So, we have a person who meets criteria for MDD, they have 5 out of 9 symptoms for a two-week period. 

We should keep in mind it’s important that the person has also suffered some loss of function in their personal or professional life because of the symptoms. This is what makes it a disorder. 

Now, what if the person also has a loss of reality-based thinking in conjunction with the major depressive episode?

This will include things like delusions and hallucinations. The delusions can be persecutory in nature or paranoid, but other types may occur too. The persecutory delusions are ones where the person feels attacked or victimized by others. They may even believe people are coming into their home to harm them. This usually presents with the patient reporting things being moved in the home or things being out of place. A common paranoid delusion is one where the person believes they are being followed. This usually presents as a car or person the patient keeps seeing, and they cannot believe that it may just be a coincidence, or someone who travels the same route to work every day.

Delusions are fixed false beliefs, and although there may be rational explanations for the things going on around them, this is the patient’s reality, and you must be careful when challenging it. The belief is fixed, and That is why presenting evidence contrary to the belief is not effective.  

The important point here is the psychotic symptoms are only present during the major depressive episode. Treat the depression and the psychotic symptoms resolve. If the psychotic symptoms remain after the major depressive episode is successfully treated, you need to reevaluate the diagnosis.

This is what separates MDD with psychotic features from schizophrenia. 

In bipolar disorder with psychotic features, the psychosis often occurs in the manic phase of the illness and has a grandiose theme associated with it. The patient my for example believe they are a prominent religious figure, or the government is plotting against them. 

We often call the delusions in depressive episodes mood congruent, meaning they are consistent with how the person is feeling. It’s not a far stretch for a person who is severally depressed to feel like people want to harm them. 

Treatment

Treatment is well established and consists of an SSRI or other antidepressant medication in combination with a dopamine blocking medication. The other option is electroconvulsive therapy (ECT) when the person is severally depressed not eating, attending to ADLs, or at risk for suicide. 

Patients should remain on medication for at least 6 months after complete resolution of symptoms. This is very important as relapse has been proven to occur when medication is stopped prior to that time. People can taper off the dopamine blocking medication after 6 months as these tend to have worse side effect profiles. The SSRI should be continued for 1 year at which time you can attempt to taper off or reach a lowest effective dose if symptoms begin to reappear. An index phase of ECT should be completed if that is the treatment of choice which consists of 12 total sessions done either 2 or 3 times per week. 

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