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.

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.

Attention Deficit Hyperactivity Disorder ADHD: Treatment

-This is one of the only disorders where medication is the first line treatment in children and adolescents.

-There is a 70%-80% response rate to psychostimulants, and medication consistently outperforms behavioral interventions in RCTs.

-For preschool age children, behavioral interventions are first line and medications are considered if there is a poor response to behavioral intervention and functional impairment. 

Psychostimulants 

Methylphenidate (MPH or Ritalin) should be started at 2.5 to 5 mg twice daily (before breakfast and lunch). It can be increased by 2.5 to 5 mg/day reaching an optimal dose of 1 mg/kg/day and a maximum dose of 2 mg/kg/day. 

Side effects include insomnia, decreased appetite, mood disturbance, tics, headaches, GI distress, and rarely psychosis. 

-There are several long-acting preparations including Ritalin XR, Ritalin LA, metadate, Concerta, Daytrana, Focalin XR and several others. The important point about long-acting preparation is they provide a sustained second release with resulting plasma levels lasting 4-12 hours depending on the preparation. 

Amphetamine sulfate (Adderall): should be started at 2.5-5 mg once or twice per day. It can be increased by 5 mg per week with an optimal dose of 0.5-1 mg/kg/day. Dextroamphetamine is twice as potent as amphetamine. The side effect profile is similar to MPH. 

Longer-acting amphetamine preparations include Adderall XR, Dexedrine, Dyanavel XR, and Vyvanse (formulated as a prodrug to reduce the risk of abuse). These will provide coverage for about 12 hours. 

-There is a black box warning for the risk of abuse and dependence. In addition, there is a cardiovascular safety warning regarding the risk of sudden cardiac death in children and adolescents with structural heart defects or other severe cardiac conditions. Patients should be screened for any cardiovascular disorders, family history of sudden cardiac death, and an EKG should be performed. 

Most Commonly Prescribed Psychiatric Medications: Desvenlafaxine/Pristiq

Desvenlafaxine is the active metabolite O-desmethylvenlafaxine (ODV) of venlafaxine and is formed as a result of CYP450 2D6. It shares many of the same properties as venlafaxine. 

  • It’s FDA approved for Major depressive disorder 
  • Mechanism of action: This medication will boost the neurotransmitters serotonin, norepinephrine, and dopamine. It does so by blocking the serotonin reuptake pump, the norepinephrine reuptake pump, and increases dopamine in the frontal cortex because dopamine is largely inactivated by the norepinephrine reuptake pump in the frontal cortex. 
  • The dosing is a little easier than venlafaxine. You can start with 50 mg/day with a maximum dose of 100 mg/day. In some cases, doses of 400 mg/day have been shown to be effective but there is increased risk for side effects at higher doses. 
  • Desvenlafaxine is more potent at the serotonin transporter but has greater norepinephrine transporter inhibition relative to venlafaxine. This is one advantage along with lower does required to achieve that inhibition. 
  • These tablets should not be broken, crushed, or chewed, it will alter the controlled release.
  • It has some of the same issues as venlafaxine when it comes to withdrawal or discontinuation. It can be difficult to taper off and may require starting fluoxetine prior to tapering. 
  • Blood pressure must be monitored regularly during treatment.
  • Most common side effects include: nausea (most common 12%), dizziness (8%), increased sweating (6%), constipation (5%).
  • Other side effects: decreased appetite, decreased libido, erectile dysfunction, abnormal dreams, tinnitus, vertigo 
  • I’ve had many questions about combining this with mirtazapine. It can be combined with mirtazapine. Trazodone and bupropion are other popular medications to combine with desvenlafaxine if monotherapy does not result in remission. 
  • Desvenlafaxine offers some benefits over venlafaxine including more consistent plasma levels due to lack of metabolism by CYP 2D6, it has more potent action at the norepinephrine transporter than venlafaxine. It may be a better option if you are targeting the norepinephrine system. 

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.  

Psychotropics: Acamprosate For Alcohol Use Disorder

I received a question asking me to discuss acamprosate as a medication and specifically to address any evidence to support its use to reduce urges to self-harm. I did the research, and this is what I found. 

The Only Medication Proven to Reduce Suicide

As a psychiatry trainee you will never forget that the two medications that reduce suicide are lithium and clozapine. In the case of clozapine, it has been shown in RCTs to reduce suicidal thoughts but not necessarily completed suicides. Lithium on the other hand has RCT data that indicates it reduces suicidal thoughts as well as completed suicide.

Lithium has anti-suicidal effects even at low doses. Lithium’s anti-suicidal effects are beneficial for both unipolar and bipolar depression. Unlike standard antidepressants that can increase the risk of suicide specifically in younger patients under the age 24, lithium has a prophylactic effect to prevent suicide. 

While lithium overdoses can be fatal, this outcome is less likely given the anti-suicidal properties of this medication. We should not avoid prescribing it for this reason. 

Psychiatrists Are More Than Just Prescribers

Introduction:

I get a lot of comments that go something like this “All psychiatrists do is prescribe medications.” Naturally, people are shocked when I talk about nutritional psychiatry, lifestyle modification, or the value of psychotherapy. I cover a lot of medication information on social media because there is significant confusion, misinformation, and a general benefit for patients to know more about the medications they routinely use. 

While medication management is a substantial portion of the work most psychiatrists do it’s not the only things we do. 

Psychotherapy

Most psychiatrists are well trained in at least one type of psychotherapy. The most common ones include cognitive behavioral therapy, interpersonal therapy, and motivational interviewing. Some are trained extensively in psychoanalysis which usually requires a 5-year commitment and engagement in psychoanalysis as a patient.

Procedures

Many psychiatrists offer procedure-based interventions such as electroconvulsive therapy (ECT), and trans cranial magnetic stimulation (TMS). We may also consult on cases of vagus nerve stimulation or deep brain stimulation used to treat severe depression. 

Neurological Disorders

As a psychiatrist you are trained to handle some of the common neurological disorders (e.g. migraine). One third of our board examination is focused on neurological disease. In rural parts of the United States sometimes there is no one else to treat these disorders and the responsibility falls to psychiatry. 

Medical Disorders

Most psychiatrists can treat things like hypertension or hypothyroidism. Many make the choice not to if the patient has a primary care physician. Like the treatment of neurological disorders sometimes there is no choice, and a psychiatrist will need to treat the medical condition. 

Social Work

Not everyone is lucky enough to have designated social workers so they can focus exclusively on the treatment of patients. We all know how important social determinates of mental health are, and sometimes altering these circumstances is the responsibility of the psychiatrist. 

Intramuscular Medication (IM) in Psychiatry: Is it Better?

Intramuscular medication as the name implies is a long-acting injectable form of medication that is usually administered into the gluteal muscle or deltoid muscle and it’s designed to take the place of PO or oral formulations.

The medications available in IM formulations

  • Aripiprazole (Abilify Maintena) 
  • Aripiprazole lauroxil (Aristada) 
  • Fluphenazine (prolixin)
  • Haloperidol (Haldol)
  • Olanzapine pamoate (Zyprexa Relprevv) 
  • Paliperidone (Invega Sustenna, Invega Trinza) 
  • Risperidone (Risperdal Consta) 

Most last between 2-4 weeks but medications like Invega trinza lasts up to 3 months 

This solves one of the major issues when prescribing medication, which is adherence with treatment. 

Notice that all these medications are first- or second-generation dopamine blockers. These medications are commonly used to treat disorder like Bipolar and Schizophrenia (serious mental illness). These populations often have difficulty with medication adherence. 

Clinically most psychiatrists will tell you IM medication improves patient outcomes. However, they may not outperform PO medication taken daily and consistently. Where these medication formulations have the biggest impact is for people who had improvement on oral medication but often forget to take medication or do not want to take medication daily. Many patients with serious mental illness stop taking medication when symptoms resolve making relapse likely. 

Side effects will be similar to the oral medication with the added logistical issue of coming to the office for the injection, and pain at the injection site. Normally we assess tolerability and risk of side effects with oral medication before giving IM medication. This avoids the potential for long lasting side effects. 

Immediate Release Vs Extended-Release Formulations in Psychiatry

Highlights From the Video

Immediate release the medication is released immediately and results is quick onset and a peak blood level. This type of formulation is generally less expensive and may be advantageous in some cases. For example, if you are using quetiapine at night in part for its sedating effects, I will use immediate release because I want a rapid effect. The same with methylphenidate or bupropion. 

The problem is this formulation requires twice a day or even three times per day dosing and results in more peaks and troughs. In general, for medications that are being used for maintenance you want consistent blood levels and not peaks and troughs.

With IR formulations, there can be more side effects and addictive potential. We believe it’s the rapid rise in blood levels of the medication that cause side effects and with medications like amphetamines for ADHD it’s the rapid rise in medication levels that can result in euphoria and thus addictive potential.

Extended release does not change the active ingredient in the medication, rather it provides a different delivery mechanism that slows the release of medication over an extended period of time. This has the opposite effect on blood levels when compared to IR. There will be less peaks and troughs and more sustained blood levels of medication. The advantage is once daily dosing and potentially fewer side effects for the pervious mentioned reasons. 

The downside is these medications tend to cost more money and some have argued when initiating these medications, a patient who has an adverse reaction will have symptoms longer with XR. Although clinically I’m not sure this is true and will generally use extended release if possible for maintenance medications.

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