My Experience with Brintellix and Anxiety - Does It Help or Worsen Anxiety?

Published 2016-09-30 06:00:00 by Michael | brintellix anxiety

Brintellix (vortioxetine) is a serotonin-modulating antidepressant that's sometimes prescribed to treat anxiety. On the other hand, a handful Brintellix patients report that Brintellix worsen's their anxiety. How can this be? This seeming contradiction highlights individual differences in how people respond to drugs.

One Psychobabble user reported:

What I noticed when I jumped from 20 to 30mg are two things: First, I feel out of it (anxious, I guess is the best description) if I miss the next 10mg dose. It is definitely some kind of withdrawal, similar to a (milder version of) Effexor. Second, it does not really open me up more, something I need. I feel "boxed in" by my anxiety. Brintellix does reduce the anxiety, somewhat. But it also has a bit of a dampening effect. Hard to describe exactly. I remember the first time I took SSRIs in the late 1990s, I felt more opened up, more able to talk and move in the world without worry. With Brintellix, that boxed in feeling is still there, despite less anxiety.

In this article, we'll discuss the use of Brintellix for anxiety (especially generalized anxiety disorder or GAD) and compare it to other treatment mainstays.

A few double-blind, placebo controlled trials have been conducted evaluating the efficiacy of Brintellix as an anxiolytic. Study results have been mixed.

To make sense of contradictory findings, Laura Orsolini et. al. conducted a metanalysis to review the evidence of the effectiveness and tolerability of vortioxetine for generalized anxiety disorder (GAD).

The authors included five studies in the metanalysis. Two studies reported that Brintellix significantly reduced anxiety whereas three studies reported negative findings.

Evidence That Brintellix Alleviates Anxiety

Takeaways From The Meta-Analysis

The key questions raised in the meta-analysis are as follows:

  • Despite many drugs on the market, response rates to initial treatment with an SSRI or SNRI are inadequate for the treatment of anxiety.
  • It remains unclear how effective vortioxetine is for "pure" anxiety disorders given inconsistent findings in randomized controlled trials.
  • Brintellix (vortioxetine) globally elevates serotonin as well as selectively binding to a variety of other serotonin receptors (5-HT3, 5-HT1D, 5-HT7, 5-HT1B, 5-HT1A - these are all serotonin receptors).
  • The antianxiety effects of vortioxetine have been consistently observed in many trials where the participants suffered from comorbid depression. Hence, vortioxetine's anti-anxiety effects may be partially related to mood improvement in patients with both depression and anxiety.
  • Vortioxetine is a partial agonist at 5-HT1A receptors. This serotonin receptor subtype plays a role in anxiety-like behaviors and vulnarability to anxiety disorders.
  • Partial agonist activity at 5-HT1B receptors affects resilience to stress, mood, anxiety, and aggression by inhibiting the release of serotonin, norepinephrine, GABA, acetylcholine and glutamate.
  • Vortioxetine blocks 5-HT1D serotonin receptors which may limit its anxiolytic potential
  • Vortioxetine blocks 5-HT3 receptors. These receptors help control gastrointestinal motility. Vortioxetine's activity at 5-HT3 may reduce anxiety-linked gastroenteric disorders.
  • Studies in animal models (e.g., mice) showed promising antianxiety effects of vortioxetine.
  • Vortioxetine's side effects are favorable with a low risk of serious drug-drug interactions.
  • Further clinical studies are needed in order to better establish vortioxetine efficacy in GAD and other anxiety disorders.

Brintellix Pharmacology

Before we get into the nitty-gritty, here's a quick fact sheet:

Brintellix Fact Sheet

Indications Major depressive disorder (MDD)
Class Atypical antidepressant
Mechanism Serotonin modulator
Common side effects Dry mouth, nausea, diarrhea, constipation, sexual dysfunction, vomiting, flatulence, dizziness
Receptor binding SERT, 5-HT3, 5-HT1D, and 5-HT7 antagonist, a 5-HT1A agonist, and a 5-HT1B partial agonist
Approval date September 2013

Brintellix vs SSRIs

Brintellix for anxiety

If you're familiar with pharmacology you might notice from the above table that Brintellix is an unusual antidepressant/anti-anxiety agent.

Most antidepressants that affect serotonin are cut-and-dry: they're SSRIs that increase serotonin by blocking re-uptake.

Unlike conventional SSRIs, Brintellix binds an array of serotonin receptors - blocking some and activating others. However, Brintellix is also a fairly potent serotonin transporter (SERT) blocker (Ki = 1.6 nM), and this action is its principle mechanism.

Brintellix is not a "pure" serotonergic agent. It also affects the other monoamines:

In animal studies, vortioxetine led to increases in extracellular levels of all five neurotransmitters in major regions of the brain associated with depression, including the prefrontal cortex and hippocampus 1.

Anxiety Disorders

Anxiety disorders are the most common psychiatric illness in the United States. They can be broken down into these subtypes:

  • generalized anxiety disorder (GAD)
  • panic disorder (PD)
  • social anxiety disorder (SAD)
  • simple phobias (SP)

Anxiety disorders tend to manifest in the mid-twenties. Women are twice as likely to be affected.

Normal Worry vs Anxiety Disorders

Anxiety is part of the human condition. It helps us avoid threatening situations. If you're standing on the ledge of a building, being anxious would have a protective effect against falling. So what counts as an disorder requiring treatment?

There are a few criteria that psychiatrists look at.

Anxiety sufferers experience exaggerated and persistent worrying or obsession about the impact of an event, an inability to relax, and difficulty concentrating. These are just a few of a wide array of symptoms that may arise from chronic, uncontrolled worrying 2.

Although anxiety disorders can't be traced to a singular cause, they are linked to:

  • Chemical signals - altered neurotransmission
  • Fight-or-flight - exaggerated sympathetic response
  • Hormones - Hypothalamic-pituitary axis (HPAA)

Neurotransmitters

Neurotransmitters are chemical messengers that allow neurons to communicate.

Neurotransmitters are released from nerve cells and bind to receptors on other cells to influence their activity. Neurotransmitters serotonin, norepinephrine, and gamma aminobutyric acid (GABA) influence feelings of well-being and the capacity to relax.

Medications for Anxiety

Like many drugs, anxiety medication tends to target the above neurotransmitters.

The most common medications for anxiety disorders include anti-anxiety medications (also known as anxiolytics), and beta-blockers. Some examples of commonly prescribed anti-anxiety medications include:

  • Benzodiazepines (e.g., Xanax)
  • Antihistamines, like hydroxyzine or diphenhydramine)
  • Selective serotonin re-uptake inhibitors (SSRIs), like Brintellix
  • Tricyclic antidepressants (less common)
  • Atypical antipsychotics (less common)

Overlap Between Anxiety and Depression

Many anti-anxiety drugs are antidepressants. There's a lot of overlap between these diseases, and antidepressants target similar processes to treat depression. Antidepressants are also typically prescribed to reduce anxiety. 3

Serotonin

First line treatments for anxiety and depression often target the serotonin or 5-hydroxytryptamine (5-HT) system in the brain.

Serotonin modulates several behaviors including mood and appetite. Although it is not completely understood how serotonin contributes to anxiety, serotonin may reduce anxiety by suppressing hyperactivity of the amygdala. The amygdala is the classic brain structure responsible for emotional responses-both elation and terror. 4

Once released, serotonin modulates the activity of different brain regions by binding to receptors. Unbound serotonin is reabsorbed by the releasing (presynaptic) cell using reuptake transporters and degraded in order to reduce serotonin concentration in the brain.

Anxiety medications typically modulate or inhibit this process to increase serotonin concentration in the brain and increase serotonin signaling.

SSRIs As Anxiety Medications

Common anxiolytics include selective serotonin reuptake inhibitors (SSRIs). These block the uptake of free serotonin and increase serotonergic tone. Serotonin and norepinephrine reuptake inhibitors (SNRIs) target serotonin, which block the uptake of both serotonin and norepinephrine. 5

A feature of anxiety disorders that has been beneficial in developing treatments is their close relationship to depression disorders. Nearly half of all patients with major depression disorder (MDD) also exhibit anxiety.

Patients with GAD also have symptoms similar to MDD. Not surprisingly, the disorders often manifest simultaneously. Similar to MDD, patients with GAD show a significant reduction in completing normal, everyday activities. Some days are completely lost due to limitations brought on by the disorder. Patients with these disorders experience a low quality of life and impairments in physical functioning, mental health, social functioning, vitality, general health and even bodily pain.

Because these disorders are so similar and antidepressants are typically used to treat anxiety disorders, this suggests that antidepressants geared at treating MDD would also be effective at treating GAD and anxiety-related disorders. 6

Brintellix For Anxiety

A novel MDD antidepressant that is currently being investigated for the treatment of anxiety is vortioxetine.

Vortioxetine is derived from halogenated benzene. It was developed as part of an initiative to generate antidepressants that target multiple pathways that contribute to depression.

How is Brintellix different from other antidepressants/anxiolytics on the market?

Its novelty stems from the fact that it modulates serotonin via multiple pathways.

  • blocking reuptake of serotonin by the serotonin transporter
  • activating serotonin receptor 5-HT1A
  • partially activating 5-HT1B, and (iv) blocking 5-HT1D, 5-HT3 and HT7 receptors.

This nuanced effect on serotonin signaling results in an increase not only in serotonin, but in other neurotransmitters like norepinephrine, dopamine and histamine.

Vortioxetine As A Cognitive Enhancer

It's not surprising that suffering from chronic aniety or depression can impair cognitive ability in the long term.

Due to its various functions, vortioxetine has also been found to improve other brain-related processes such as learning and memory. Because its function is not completely understood, vortioxetine may modify activation of other neurotransmitter receptors and have other unknown beneficial effects. 7

Vortioxetine was approved by the US Food and Drug Administration (FDA) on September 30, 2013 to treat MDD in adults. It is now sold under multiple brand names including Trintellix and Brentillix which contain the beta polymorph of vortioxetine hydrobromide.

Chemical Properties

Vortioxetine is a white, slightly beige powder that is partially soluble in water. However, it is supplied in the form of an immediate-release tablet with 5, 10, 15 or 20mg of vortioxetine that is taken orally.

Half-Life

It has a long half-life of approximately 66 hours. Thus, a steady state concentration can be reached in approximately 2 weeks after administration of the initial dose.

Onset of Therapeutic Effects

In the case of MDD, vortioxetine is not typically effective until 6 to 8 weeks following the initial treatment. Patients are started on 10mg per day and if it is well-tolerated, the dose increases to 20mg per day since higher doses are more effective. 8

Common Side Effects

Since blocking serotonin receptors can result in light headedness and nausea, it is no surprise that the most common side effects when treating GAD were nausea and headaches. Nausea was especially common after high doses. Also reported: - diarrhea - dry mouth - constipation - vomiting - dizziness - abnormal dreams

Sexual dysfunction in a small percentage of men has also been reported. 9

Although not approved to treat anxiety, there are several studies that have examined the effects of vortioxetine on anxiety.

A recent study of patients with regular or high MDD-associated anxiety symptoms found that 10mg and 20mg per day of vortioxetine decreases anxious mood and somatic anxiety. For patients with MDD-associated with a higher level of anxiety, anxiolytic effects were not observed as soon as in patients with lower levels of anxiety. However, the effect on anxiety was similar 10.

References

  1. D'agostino A, English CD, Rey JA. Vortioxetine (brintellix): a new serotonergic antidepressant. P T. 2015;40(1):36-40.

  2. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024919/. Accessed August 5, 2016.

  3. Craske MG, Rauch SL, Ursano R, Prenoveau J, Pine DS, Zinbarg RE. What is an anxiety disorder?. Depress Anxiety. 2009;26(12):1066-85.

  4. Nicholson SL, Brotchie JM. 5-hydroxytryptamine (5-HT, serotonin) and Parkinson's disease - opportunities for novel therapeutics to reduce the problems of levodopa therapy. Eur J Neurol. 2002;9 Suppl 3:1-6.

  5. Menting JE, Honig A, Verhey FR, et al. Selective serotonin reuptake inhibitors (SSRIs) in the treatment of elderly depressed patients: a qualitative analysis of the literature on their efficacy and side-effects. Int Clin Psychopharmacol. 1996;11(3):165-75.

  6. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024767/. Accessed August 5, 2016.

  7. Boulenger JP, Loft H, Olsen CK. Efficacy and safety of vortioxetine (Lu AA21004), 15 and 20 mg/day: a randomized, double-blind, placebo-controlled, duloxetine-referenced study in the acute treatment of adult patients with major depressive disorder. Int Clin Psychopharmacol. 2014;29(3):138-49.

  8. D'agostino A, English CD, Rey JA. Vortioxetine (brintellix): a new serotonergic antidepressant. P T. 2015;40(1):36-40.

  9. Davidson JR, Feltner DE, Dugar A. Management of generalized anxiety disorder in primary care: identifying the challenges and unmet needs. Prim Care Companion J Clin Psychiatry. 2010;12(2)

  10. Bystritsky A, Khalsa SS, Cameron ME, Schiffman J. Current diagnosis and treatment of anxiety disorders. P T. 2013;38(1):30-57.

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