The Truth About Anxiety Treatments: What Really Works 

In the first part of this series, we discussed anxiety and specifically generalized anxiety disorder (GAD) as a diagnosis. Now we are going to look at the research associated with the treatment of GAD and let the research inform our decision making about what works when a person presents with GAD. Some of these findings may surprise you. 

SSRIs 

Although the effect size of SSRIs in GAD is small, 0.33 they remain the recommended first line option for treatment. It’s also important to confirm that someone has had an adequate trial of SSRI treatment before assuming it’s not effective. The choice of which SSRI will depend on the side effect profile and other patient factors such as presence of insomnia, substance use, or pregnancy. Escitalopram is a good place to start, fluoxetine, or sertraline can be alternative options. Although paroxetine has the FDA approval for GAD it has more side effects like weight gain and sedation, along with several other factors that make this medication a poor first-line option. If the first medication trial is ineffective it’s reasonable to try a second SSRI or switch to the SNRI duloxetine. 

When SSRIs Don’t Work

The next step in many cases is to try a medication from a different class. Two SNRIs have been well studied in GAD, venlafaxine, and duloxetine. Venlafaxine is not considered a first line choice due to the side effect profile and the small increase in efficacy. From the meta-analysis on anxiety treatments the effect size is 0.36 slightly better than the SSRIs but it would likely be undetectable clinically. Duloxetine is slightly better with respect to side effects and can be a good choice if you chose to use an SNRI for anxiety treatment. It has the added benefit of lower risk for sexual side effects compared to venlafaxine and possibly improved cognition.

Bupropion in Anxiety Disorders

There is some evidence for the use of bupropion in GAD. In one study small study of 25 participants bupropion beat the SSRI escitalopram head-to-head. Other lines of evidence include more improvement in GAD when bupropion was added as a combination treatment with SSRIs compared to adding buspirone. For clarification the effect size of buspirone in GAD is 0.17 which would be unlikely to produce any observable clinical improvement in anxiety symptoms. I largely stay away from buspirone unless it’s used to treat sexual side effects of SSRIs. Bupropion may be good option for patients who do not want the side effect profile of an SSRI. Although we lack the large RCTs for bupropion in GAD there is some evidence to support its use. The negative studies indicating bupropion worsened symptoms of anxiety come from studies in panic disorder where bupropion was found to worsen panic symptoms. 

What About New Antidepressants?

Vortioxetine had a lot of hype when it first came out, and many believed it would work for GAD. Unfortunately, like many medications when we believe something should theoretically work based on the mechanism of action, we are sadly disappointed. This is one of those cases. The effect size was found to be 0.12 and it did not even cross into the small range. This medication performed worse than buspirone for GAD.  

Vilazodone also had one positive study published for GAD. Again, based on the MOA it should work just fine, it has typical SSRI like effects in addition to 5-HT1A effects like buspirone, you should get the best of both worlds theoretically. This one positive study was followed by two distinctly negative studies and a calculated effect size of 0.26 which is considered small. 

Both were not submitted for FDA approval for GAD based on the negative results. 

The Hydroxyzine Argument

Hydroxyzine is an antihistamine that’s been out for a long time. As I stated earlier it has approval for tension associated with psychoneurosis which is the old psychanalytic way of describing anxiety. It’s often seen as ineffective, but the effect size was higher than SSRIs and SNRIs for the treatment of GAD. Hydroxyzine had an effect size of 0.45, and we may want to reconsider the use of this medication. Some limitations are the size of the studies and duration of the studies, but this still provides a fair amount of evidence that hydroxyzine may perform better than we think. 

Quetiapine Surprised Me

Quetiapine is an antipsychotic medication usually not considered as a treatment option for anxiety disorders. However, the effect size was large with a range from 1.0 to 2.2. To put this in perspective this medication outperformed SSRIs, SNRIs, and benzodiazepines. Why did it not gain FDA approval? If you watched my other videos, you should know that the side effect profile is difficult to tolerate. Metabolic side effects and sedation are common, and the FDA does not view anxiety disorders as significant enough to warrant this degree of risk. One place where this medication may be very useful is in bipolar disorder with severe anxiety. We avoid antidepressants in this population at all costs, quetiapine offers a good option with strong evidence and strong antidepressant effects in bipolar depression. 

Where this fits in clinical practice for me is as a 3rd or 4th line option after all other avenues have been explored except for bipolar disorder as stated above. The antipsychotic medications have been known to have a positive effect on anxiety, but the limitation remains side effects. 

Anxiety as a less Severe Form of Psychiatric Illness

According to the FDA medications like aripiprazole and quetiapine are reasonable adjunctive therapies for patients with major depression that does not respond to first line treatment options. This is not their view for anxiety disorders that respond poorly to first line options. When we look at disability caused by depression and anxiety there isn’t much difference in the odds of being disabled for depression vs anxiety (3.5 Vs 3.1). For whatever reason we continue to view anxiety as less significant although DSM does not identify a clear diagnostic hierarchy. 

Things like psychotherapy are often recommended as first line options. In the 1980’s when GAD was first conceived, it was thought to be a mild disorder where psychotherapy is the most effective treatment. In fact, psychotherapy did well it had an effect size of 0.5 which is nearly the same as benzodiazepines. Psychotherapy is a good place to start for anyone presenting with an anxiety disorder. I’m also a big believer of combining psychotherapy and medication for anxiety disorders. 

What about Benzos?

Benzodiazepines can have all sorts of effects on the body. Largely we think of the benefits of benzodiazepines in anxiety disorders as having a major effect on the physical symptoms of anxiety and not so much on the chronic worry that characterizes the disorder. Many of the effects of benzodiazepines would not be measured by traditional anxiety rating scales based on the updated conception of GAD. Nevertheless, Benzodiazepines had an effect size of 0.4-0.5 which falls into the moderate range for GAD. 

A final Option to Consider

Silexan the proprietary extract of Lavender oil has good evidence and a large effect size when used to treat GAD. In Germany there is a respect for the power of natural products, and they are regulated and prescribed in the same manner as pharmaceutical drugs. When silexan was studied in GAD the effect size can range from 0.5 to 0.9. This is a large effect size and I have another video that covers Silexan in detail if you are interested. This can be added to most medication regimens without significant drug interactions and has even been shown to decrease the use of benzodiazepines in those who are using them for GAD. It can be purchased under the brand Name Calm Aid for around $30 per month, and if you are wondering I get no financial compensation for saying this I’m just presenting the evidence. 

Conclusion

We covered a lot here today and I think one of the most important points to stress is the importance of finding the underlying cause of anxiety symptoms. I believe anxiety is driven by other underlying factors as discussed at the beginning of the video. There are many reasons to be anxious and all require a different approach. Without this clarification the patient is likely to continue struggling. Another important point is theoretical mechanism of action that should work, do not always work as seen in the case of vilazodone. We also had some surprises, hydroxyzine, and silexan performed very well but traditional first line options such as SSRI and SNRIs were not so great. I hope this discussion was helpful and if you want more content on anxiety disorders, let me know below in the comments section. 

The Rise of Generalized Anxiety Disorder 

Anxiety is pervasive in the world today. All of us including me know what it’s like to be anxious. We have all read recent articles about how the COVID-19 pandemic increased anxiety around the world, and this has placed a lot of focus on anxiety as a psychiatric diagnosis. Anxiety in my opinion is not an independent disease the way the diagnostic and statistical manual (DSM) would lead you to believe. Anxiety is a symptom that has various potential causes and that’s what we are here to talk about today. 

This is inspired by a real case where I needed to do a deep drive into the literature to understand the root of anxiety and its treatments. I hope you guys enjoy the topic.

Introduction 

Generalized Anxiety disorder has been revised significantly over the years by the DSM. It seems like no one knowns what GAD is, or if it’s an independent disease state. The DSM only provides descriptive criteria and does not comment on the underlying cause of anxiety. Prior DSM criteria from DSM III focused more heavily on autonomic and motor symptoms of anxiety. In these editions, what is now GAD was referred to as psychoneurosis an old Freudian term that fell out of favor as we moved away from psychoanalysis. Interesting fact, if you look up the indication for hydroxyzine in anxiety it still states “for tension associated with psychoneurosis.” The more recent updates in DSM have stepped away from these physical symptoms and focused more on the mental state of chronic and excessive worry. If we attempt to apply older studies on anxiety treatment to the current DSM criteria, they may not be valid. 

What I want to stress, is worrying is the core symptom of GAD now with at least 3 out of 6 of the following: 

-Restlessness 

-Being easily fatigued 

-Difficulty concentrating 

-Irritability 

-Muscle tension 

-Sleep disturbance include insomnia 

When I look at the criteria, they look a lot like depression to me. I often argue to my residents and medical students that it’s hard to separate depression and anxiety, but they usually disagree, so this video is for them as well. 

Causes of Anxiety 

We should try and figure out what the potential underlying causes are for anxiety. Since the DSM does not guide us here, we need to think through each possible cause. 

Personality: people often underestimate the importance of personality traits in psychiatry. One personality trait that is part of the “big 5” is neuroticism. We all have anxiety as a personality trait, some individuals have more some have less, but for the most part there is a normal distribution in the population. If you have more, you tend to get diagnosed as having a “anxiety disorder.” Most people fall in the middle we have some anxiety under specific circumstances but not enough for it to be identified as pathology. 

Depression: As I stated before there is a lot of overlap in the criteria for depression and generalized anxiety disorder. In fact, the same medications are used to treat both disorders. Depression can clearly be a cause of anxiety. 

Mania: people often mistakenly believe that people in manic states are having fun and love being that way. This is not true, and anxiety can be one of the potential symptoms associated with manic states. 

Psychosis: Schizophrenia or schizoaffective disorder can be anxiety provoking disorders 

PTSD: Excessive worry can be a part of PTSD 

Eating Disorders

Substance Use Disorders 

OCD

Other environmental factors can cause anxiety independent of those listed above: life stages, divorce, death of a loved one, diagnosis of severe physical illness, significant loss of physical function from an injury 

The point here is there are many things that could result in a state of high anxiety. What you should start to see here is once we rule out all these causes for anxiety there would be no way to diagnose an independent anxiety disorder. 

Just describing the symptoms of anxiety checking the boxes for the criteria and labeling someone as having “anxiety disorder” does not have much meaning. We have to say what the underlying cause of the anxiety is to treat the symptoms effectively. 

Myths About Medication in Anxiety Disorders

People often believe that anxiety responds faster to medication than depression. This is not true the response to medication takes the same amount of time for both anxiety and depression. This provides another layer of evidence that GAD can be driven by depressed states. Trials of medications such as SSRIs can last several weeks as doses are titrated until the individual has an acceptable level of response to the medication. 

There is also no established dose dependent response in GAD. Some believe that GAD responds better to higher doses of SSRIs, say 40 mg of escitalopram. This has not been established in the research literature. This may also indicate that the underlying cause is OCD which traditionally requires higher doses and longer duration of treatment. 

Many people presenting with anxiety will be started on an SSRI. In the past paroxetine was favored by primary care because it had the FDA indication for use in anxiety disorders. I never think paroxetine is the correct choice for anxiety due to the side effect profile which includes risk for withdrawal and harm during pregnancy. Citalopram has suffered a similar fate as dose dependent QTc prolongation limits the doses we can use in clinical practice. Escitalopram can prolong QTc at higher dose above the approved maximum but there is significantly less risk at standard doses. 

How effective are these medications for anxiety disorders? Not very, a meta-analysis found that SSRIs have an effect size of 0.33 falling into the low range. 

Part Two:

Part two of this series will be coming soon. I had way too much to say about the diagnosis of GAD that I didn’t leave any time to discuss treatment. Part two will included a detailed analysis of medications for GAD.

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. 

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 

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.

   Why It’s Important to Thrive and Not Just Survive

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

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

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

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

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

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

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

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

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

Let’s Look beyond the absence disease 

Lifestyle Psychiatry and the Gut Microbiome

  • The gut microbiome consists mostly of bacteria and that is largely the portion of the microbiome we are focusing on (fungi and viruses exist but their function is largely unknown) 
  • Communication pathways exist between the microbiota-gut-and brain. 
  • Multiple mechanisms exist that allow gut microbiota to signal to the brain and control physiological processes. 
  • These include release of gut peptides from enteroendocrine cells which activate receptors of the immune system and vagus terminals in the gut. 
  • Studies indicate that these bacteria can manufacture and secrete essential neurochemicals including serotonin, dopamine, NE, GABA, and acetylcholine 
  • Depression and anxiety have been linked to a less well diversified gut microbiome.
  • What can help diversify the gut microbiome? Diet, processed food, sugar, saturated fats, and red meat. Medication can also alter the gut microbiome, a good example is oral antibiotics used to treat an acute infection, sleep, exercise. Sounds a lot like a healthy lifestyle will get you the microbiome you need for optimal mental health. 
  • However, if you want a treatment there have been several studies that looked at fecal transplant to treat psychiatric disorders. Fecal transplants are much easier these days and now there is a capsule version that you take orally. There is not enough data to recommend this as a practical treatment and if the patient goes back to eating a poor diet, sleeping poorly, not exercising then the gut microbiome will revert after the transplant. 
  • What are the practical things you can do? Stop eating processed food, sugar, and red meat. Increase your fiber intake and select a diet like the Mediterranean diet or a plant based whole food diet that will provide those prebiotics. You could supplement with a probiotic but most of what you need can be had from a good diet alone and I think it’s far better to change the diet then to try using supplements to treat a poor diet. Fermented products like kimchi, kombucha and sauerkraut are good sources of live bacteria.
  • If you choose to take a probiotic make sure it’s a quality, 3rd party tested product. 
  • Increase aerobic activity, I think if you goal is overall general health and you have limitted time, I think aerobic activity is a better bang for your buck. 
  • The way I believe you get and keep a healthy gut microbiome is through lifestyle modification. Improving your diet, exercise, and sleep is a good place to start. If you want to supplement with food products like kimchi or kombucha, go for it. I do not believe there is enough evidence to support a probiotic supplement for psychiatric disorders at this point, but if you want to spend $30 or more per month on a product if it’s a quality one that’s fine. Remember you cannot supplement away a bad diet. 

Why Psychiatrists do not Wear White Coats

I trained in a location where white coats were never worn by psychiatrists. I only wore mine during the professional photos on the first day of residency. From that point forward it remained in my closet. 

The choice to discard the white coat always made sense to me, because I believe one of the most healing aspects of psychiatry is the physician patient relationship. One way to enhance that relationship is to make my patients feel as comfortable as possible. There is a concept in primary care called “white coat hypertension” where some patients have increased blood pressure only when coming to see their doctor. In psychiatry you can imagine a similar scenario. Some patients experience severe anxiety prior to the initial encounter. Others have had previous bad experiences with psychiatrists making them more prone to this “white coat syndrome.”

My goal is to have a meaningful conversation with my patients, and some of the material we discuss is very sensitive. There is no reason to make that conversation any more intimidating than it already is. Everything from my style of interviewing, to dress is meant to be casual to help establish trust. Trust is an important foundation for any relationship and is critical for any physician patient relationship. 

I detached myself long ago from white coats as a symbol of knowledge or prestige. I trust in my skills as a physician and allow those skills to speak for themselves. 

Grounding Technique For Anxiety

Anxiety is something most of us have experienced. This five-step exercise can be helpful during periods of anxiety by helping to ground you in the present moment. 

Start the exercise by drawing attention to your breathing. Slow, deep, breaths can help you induce a feeling of relaxation. Once you feel relaxed, go through the following steps to ground yourself: 

One: Note ONE thing you can taste

Examples may include: gum, sugar free candy, coffee, sparkling water (anything you can taste in the moment). 

Two: Note TWO things you can smell 

Examples may include: fresh air, scented candle, flowers, food cooking (anything around you that you can smell)

Three: Note THREE things you can hear 

Examples may Include: people talking, cars driving, wind blowing, rain falling (anything in the environment you can hear) 

Four: Note FOUR things you can touch 

Examples may Include: desk, chair, pen, phone (anything around you that you can touch) 

Five: Note FIVE things you can see 

Examples may include: door, computer screen, car, tree, house (anything you see around you)

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