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. 

Malingering In Psychiatry

  • Let’s first define malingering, this is the production of false or grossly exaggerated physical or psychological symptoms motivated by external incentives. 
  • Not all lying involves secondary gain, but ALL malingering does involve secondary gain 
  • Common secondary gains include avoiding military service, avoiding work, financial incentives, avoiding legal actions, and obtaining controlled substances 
  • Feigning mental illness is not the same as malingering because the reason behind the false production of symptoms is not assumed with feigning symptoms. 
  • Factitious disorder is the voluntary production of symptoms, but this is with the goal of assuming the sick role or role of a patient, it’s not done for secondary gain. 

Consider malingering when….

-Rare symptoms are present 

-Improbable symptoms are being reported

-Rare combination of symptoms are present

-Reported Vs observed symptoms are not congruent

Malingered Depression:

-25-30% of patients who claimed major depression in civil litigation were probably malingering

-Pay careful attention to facial expressions 

-Pay careful attention to motor function, psychomotor retardation is an important observable sign

-If appetite changes are reported look for actual objective weight change 

-symptoms opposite of depression 

-blaming others for everything is not the way guilt typically presents in depression, this is externalizing and not taking personal responsibnility

Malingered Psychosis: 

-Often in true psychosis people can describe the voice/s, is it loud, soft, male, female, you have some experience of what you heard. When you ask a malingering patient about a voice, they should have some ability to describe what they are hearing, if not consider malingering.

-If you are suspicious, begin with open ended questions, ask them to describe things in their own words. 

-Genuine AH are in words or sentences, drug Hallucinations usually occur as unformed noises.

-The location of the voice inside the head or outside is no longer a good predictor of malingering 

-Many times the content of voices are derogatory in nature

-Other signs of malingered psychosis include Vague or inaudible auditory hallucinations, AH not associated with delusions (86% of AH have an associated delusion), no strategies to diminish voices 76% of patients have some coping strategy to diminish the voices. They claim that all instructions are obeyed, the hallucinations are visual alone, seeing little people or giant people for example.

Lamotrigine/Lamictal is It Really Effective in Bipolar Disorder?

There are a lot of good things about lamotrigine, and it’s commonly used in both the adult and child adolescent population. The question is how effective is lamotrigine at treating mania, and bipolar depression? I will answer this and provide an in-depth overview of the medication here in this video. Timestamps

Introduction: 00:00 to 00:35

Indications and a discussion on negative studies: 00:36 to 04:55

Mechanism of Action: 04:56 to 06:10

Dosing: 06:11 to 08:19

Side Effects: 08:20 to 12:48

Final Comments: 12:49 to 15:38

Most Commonly Prescribed Psychiatric Medications: Trazodone

  • The only FDA approved use of trazodone is for depression. However, this medication is rarely prescribed for this purpose. The higher dose requirements and lower affinity for the serotonin transporter allows the side effect profile to make the medication intolerable for most patients. 
  • The most common way it’s used is as an adjunctive therapy for sleep disturbances secondary to depression. 
  • The mechanism of action is blockade of serotonin 2A receptors and blockade of the serotonin reuptake pump. 
  • Dosing: To take advantage of the sedating properties you want to use a lower dose. A dose of 25-150 mg/night is appropriate. For depression the dose must be much higher anywhere from 150-600 mg/day 
  • For depression start with 150 mg/day in divided doses (short half-life) and increase every 3-4 days by 50 mg/day as needed to a target dose of 400 mg/day. For insomnia start with 25-50 mg/night and increase as tolerated to a target dose of 50-150 mg/night. That same target range of 50-150 mg/day can be used if trazodone is being added as an adjunct therapy for depression. 
  • It’s very important to start low and go slow when increasing the dose. Patients can have carryover sedation, ataxia, and intoxicated like feeling if titrated too rapidly. 
  • Do not stop the medication prematurely. In difficult to treat patients’ higher doses may be required 150-300 mg or up to 600 mg in some cases. 
  • It’s ideal to try and limit dosing to once nightly at bedtime to avoid daytime sedation 
  • Notable Side effects: Nausea, vomiting, constipation, dry mouth, dizziness, sedation, fatigue, headaches, life threatening side effects include priapism (1 in 8,000 men), seizures, activation of suicidal ideation in patients under 24 years of age.
  • The onset of therapeutic actions for insomnia should be immediate once an adequate dose is reached. There is no evidence of tolerance, abuse potential, or withdrawal
  • Therapeutic action for depression is delayed by 2-4 weeks if it’s not working by 6-8 weeks consider a dosage increase or switch depending on dosage reached 
  • Trazodone offers a nonaddictive option for insomnia treatment and can be used as an adjunct for depression treatment. It’s less likely than other antidepressants to cause sexual dysfunction. It may be less likely to precipitate hypomania or mania and may have some benefit for treating agitation and aggression associated with dementia. 

Most Commonly Prescribed Psychiatric medications: Seroquel or Quetiapine

  • Quetiapine offers some benefits over other dopamine blocking medications. It has a much lower risk for EPS and a broad spectrum of effects. The main limitations are weight gain, sedation, and orthostasis. The extended-release formulation offers a once nightly dosing that can reduce daytime sedation. 
  • It has a number of FDA approved indications including use in schizophrenia, bipolar disorder, bipolar depression, and major depression as an adjunct 
  • It’s mechanism of action is blocking dopamine D2 receptors which targets positive symptoms of psychosis and serotonin 2A receptors which enhance dopamine release in certain regions of the brain reducing motor side effects and possibly improving cognitive side effects. It’s effects on depression and bipolar depression may be related to 5HT1A partial agonist activity, norepinephrine reuptake blockade, and 5HT2C and 5HT7 antagonist properties.
  • Clinically quetiapine is often underdosed and stopped or switched before an adequate trial is completed. Higher doses generally achieve greater response for manic or psychotic symptoms. 
  • For schizophrenia start with 25 mg BID or 300 mg XR QHS. Target doses 400-800 mg/day 
  • For bipolar start with 50 mg BID or 300 XR QHS. With a target dose of 400-800 mg daily for mania and 300 mg/day for depression (studies indicate that 600 mg was not better for depression than 300 mg)
  • For depression start at 50-100 mg/day in divided doses with a target of 150-300 mg/day (data indicates that 150 mg and 300 mg do equally well so either dose is appropriate depending on patient response) 
  • You can increase the dose 50-100 mg/day every 1-4 days to a target dose 
  • The max daily dose in adults is 800 mg/day, occasionally patients may require 800-1,200 mg/day for psychosis or mania 
  • Monitoring is similar to other dopamine blocking medications, specifically fasting blood glucose and lipid profile, BMI, blood pressure 
  • Side effects include sedation, hypotension, dry mouth, dizziness, constipation, weight gain and fatigue. Watch for orthostatic hypotension at high doses or with rapid titration. There is essentially no motor side effects or prolactin elevation. 
  • For XR formulations do not crush or chew them, if a patient has been off the medication for more than 1 week you want to restart as if initial therapy. Quetiapine has some abuse potential reported in the literature particularly in incarcerated populations 
  • In the initial studies with beagle dogs cataracts developed but human studies have not shown this association 

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. 

Pramipexole for Treatment Resistant Depression

How to use Pramipexole

  • Selective D3 agonist thought to be related to hedonic drive. 
  • FDA approved for Parkinson’s disease and restless leg syndrome 
  • 5 randomized controlled trials indicating effectiveness in depression as monotherapy or adjunctive therapy and in bipolar disorder as adjunctive therapy with a mood stabilizer 
  • Side effects; nausea, hypotension, and fatigue, titrate slowly and give the dose at night 
  • Start with 0.125-0.25 mg QHS and rise by 0.25 mg every 5-7 days towards a target dose of 0.75-2 mg QHS 
  • Watch for hedonistic homeostatic dysregulation (HDD) including pathological gambling and shopping

5 Stage Method for Treatment Resistant Depression (TRD)

I get a lot of questions that go something like this, I’ve been on X, Y, Z medications and nothing seems to help. It seems that what most are asking about is what is the algorithm for treating depression and when does it become treatment resistant. This video will provide a look at what treatment resistant depression is and provides a 5-stage strategy to medication selection.  

Schizoaffective Disorder: A Confusing Diagnosis

Introduction: 

  • Schizoaffective disorder has features of both schizophrenia and mood disorders (bipolar and depression). 
  • Two sub types: depressed type and bipolar type 
  • The diagnosis can get complicated because primary mood disorders can have psychotic features (MMD with psychotic features or bipolar disorder with psychotic features), patients with schizophrenia can have mood symptom most commonly depression. 

Epidemiology:

  • The lifetime prevalence is less than 1%, the most recent data indicates 0.3% but I would say there is a range between 0.5-0.8%
  • More women have the depressed type greater than 2:1 ratio 
  • Equal number of men and women have the bipolar type 
  • The cause of schizoaffective disorder is unknown. It may be a type of schizophrenia, a type of mood disorder, but most likely it’s a spectrum that combines all these things.
  • Schizoaffective disorder has a better prognosis than schizophrenia but a worse prognosis than primary mood disorders. 
  • Patients are said to have a nondeteriorating course and respond better to lithium than patients with schizophrenia. 

Diagnosis:

  • Schizoaffective disorder combines the features of both schizophrenia and affective mood disorders. 
  • If the mood is primarily manic, it’s called schizoaffective disorder bipolar type 
  • If the mood is primarily depressed it’s called depressed type 
  • The mood component should be present for the majority > 50% of the total illness 
  • You must have a two-week period where psychotic symptoms and are present in the absence of mood symptoms

Treatment:

  • Treatment will depend on the predominant symptoms. If the patient has more mania than a mood stabilizer will be used (e.g., lithium) 
  • For psychotic symptoms, dopamine blocking medications will be used (e.g., risperidone) 
  • For depressive symptoms serotonin reuptake inhibitors will be used (e.g., sertraline)

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