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VORTIOXETINE: CLINICAL ADVANTAGES OF USING ORAL DROP SOLUTION (ODS)

Giovanni Martinotti

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Cattedra di Psichiatria

Università “G.d’Annunzio” Chieti, Italy

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Department of Pharmacy, Pharmacology and Clinical Sciences, University of Hertfordshire, UK

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Vortioxetine: resons behind its use in my clinical experience

Vortioxetine ODS: advantages

Case studies

AGENDA

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THE MULTIMODALITY OF VORTIOXETINE

VORTIOXETINE: A NEW ALTERNATIVE FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER, SALAGRE ET AL.,2018

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THE MULTIMODALITY OF VORTIOXETINE

STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY

SERT inhibitor

5-HT1A agonist

5-HT1B partial agonist

5-HT1D antagonist

5-HT3 antagonist

5-HT7 antagonist

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Vortioxetine versus comparator: there is a numerically higher probability of remission in favor of vortioxetine versus sertraline (RD, 14.4%), venlafaxine XR (RD, 7.2%), bupropion SR (RD, 10.7%), and citalopram (RD, 16.8%)

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THE REASONS WHY I’M USING VORTIOXETINE:

1. Vortioxetine in young and drug-naive patient:

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  • Efficacy
  • Few side effects

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WHY NOT TRYING THE ANTIDEPRESSANT THAT GIVES ME THE BEST PROFILE BETWEEN EFFICACY AND TOLERABILITY?��

EFFICACY

TOLERABILITY

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Current Neuropharmacology, 2022

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THE REASONS WHY I’M USING VORTIOXETINE:

2. Vortioxetine in patients experiencing anhedonia and affective blunting with other antidepressants

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Compared to controls, patients reported significantly (p<0.05) less ability to cry, irritation, care about others' feelings, sadness, erotic dreaming, creativity, surprise, anger, expression of their feelings, worry over things or situations, sexual pleasure, and interest in sex.

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Emotional blunting may be an under-appreciated side-effect of SSRIs that may contribute to treatment non-compliance and/or reduced quality of life.

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Mean difference in change from baseline for vortioxetine versus placebo for (A) MADRS total score, (B) MADRS anhedonia subscale score, (C) SDS total score, and (D) SDS social-functioning score.

McIntyre et al., 2021

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EFFECTIVENESS OF VORTIOXETINE ON EMOTIONAL BLUNTING

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THE REASONS WHY I’M USING VORTIOXETINE:

3. Vortioxetine in patient with dual diagnosis:

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  • No specific pharmacokinetic interaction also in subjects with hepatic problems
  • No specific effect on QTc and other cardiological issues
  • No anhedonia and affective blunting which represent risk factors for craving and relapses

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EFFECT OF VORTIOXETINE ON PHARMACOKINETICS AND PHARMACODYNAMICS OF ETHANOL

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EFFECTIVENESS AND TOLERABILITY OF VORTIOXETINE IN DUAL DEPRESSION

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  • 57 MDD+AUD and 56 MDD outpatients, matched for baseline characteristics.
  • Patients were assessed after 1, 3, and 6 months-treatment with vortioxetine (10-20 mg/daily, flexibly dosed) in combination with continuous psychosocial support.
  • The primary outcome was improvement in depressive symptoms measured by the Montgomery-Åsberg Depression Rating Scale.
  • Changes in anxiety, anhedonia, cognition, functioning, quality of life, were also evaluated

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  • Vortioxetine significantly improved mood in MDD+AUD patients (p<.001), with no differences when compared to MDD (p=.36).
  • A substantial rate (45.6%) of comorbid subjects obtained clinical remission at endpoint (p=.36 vs. MDD).
  • Baseline to endpoint improvements of all secondary outcomes (p<.001), with no significant difference between groups, were observed.
  • Overall, vortioxetine was safe and well-tolerated.

Di Nicola et al., 2020

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EFFECTIVENESS OF VORTIOXETINE IN DUAL DEPRESSION

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  • The efficacy of vortioxetine could be mediated by an effect on cognition (5-HT-7)
  • In the patient who uses substances, cognitive control mediated by the dorsolateral pre-frontal cortex plays a decisive role in the management of craving, the latter supported by dopaminergic mechanisms inherent in the nucleus accumbens and other circuits pertaining to the brainstem
  • The ineffectiveness of pharmacological therapies used to reduce craving for substances probably lies in the difficulty of modulating the nucleus accumbens with direct mechanisms
  • Vortioxetine could exert its effect on craving indirectly, with the same principle that brain stimulation techniques on the dorsolateral prefrontal cortex are able to reduce craving and substance use

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Explanatory mechanisms able to justify the effect of vortioxetine in dual depression

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  • The classic antidepressants, primarily SSRIs, cause affective blunting. This experience could cause/facilitate the desire to take substances or alcohol capable of "relaxing" the emotional detachment perceived by patients
  • It is for this reason that many studies have not demonstrated positive results in the management of addictions associated with depressive spectrum disorders, with sometimes even worsening results with respect to the possible induction of relapses despite an improvement in depressive symptoms
  • Vortioxetine has been shown not to cause the flattened affect typically observed after SSRI use, nor to worsen the anhedonic features already characteristic of a patient with alcohol or substance use disorder in remission
  • This specific mechanism may contribute to the efficacy of vortioxetine in dual depression

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Explanatory mechanisms able to justify the effect of vortioxetine in dual depression

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THE REASONS WHY I’M USING VORTIOXETINE:

4. Vortioxetine in elderly patient:

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  • Beneficial effects on cognitive functions
  • No interactions with other drugs
  • Safe with medical comorbidities

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VORTIOXETINE TABLETS VS. DROPS:

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ADVANTAGES AND PITFALLS��

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REAL- WORLD STUDY IN SWITZERLAND: EFFECTIVENESS AND TOLERABILITY OF VORTIOXETINE (TABLETS AND DROPS) IN THE TREATMENT OF MDD

Figure 1. Comparable distribution of patients with first and previous depressive episodes: a majority of all patients are experiencing moderate depressive severity.

BRINTELLIX EXPERIENCE 18431N / SUB-ANALYSIS TABLETS VS. DROPS, ANALYSIS SET 20.01.2023, DATA ON FILE

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Table 1. Description of patient disposition

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BRINTELLIX EXPERIENCE 18431N / SUB-ANALYSIS TABLETS VS. DROPS, ANALYSIS SET 20.01.2023, DATA ON FILE

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Mean dose over the course of observation: 10 mg dose was the highest, followed by 20 mg dose

Figure 2. Patients on tablets (78%) vs

oral drops (22%)

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REAL- WORLD STUDY IN SWITZERLAND: EFFECTIVENESS AND TOLERABILITY OF VORTIOXETINE (TABLETS AND DROPS) IN THE TREATMENT OF MDD

Figure 3. Mean severity of depression at start of treatment was 34.2, according to the sum of MADRS items; the mean change over 8 weeks was -20.6 (LOCF)

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BRINTELLIX EXPERIENCE 18431N / SUB-ANALYSIS TABLETS VS. DROPS, ANALYSIS SET 20.01.2023, DATA ON FILE

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Figure 4. At the end of the observation period (visit 4, week 8) there was an improvement in every single domain at the MADRS

BRINTELLIX EXPERIENCE 18431N / SUB-ANALYSIS TABLETS VS. DROPS, ANALYSIS SET 20.01.2023, DATA ON FILE

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SUB-ANALYSIS: SIMILAR EFFICACY BETWEEN DROPS VS TABLETS�

BRINTELLIX EXPERIENCE 18431N / SUB-ANALYSIS TABLETS VS. DROPS, ANALYSIS SET 20.01.2023, DATA ON FILE

Similar efficacy between Drops vs Tablets, based on total MADRS score, and each individual domain of MADRS (p-values; no significant differences)

Change in total MADRS score at Visit 4 from Baseline

n=174

Tablets

Drops

Change in MADRS single items at Visit 4 from Baseline

Visible Sadness

Reported Sadness

Inner Tension

Insomnia

Loss of Appetite

Difficulty Concentrating

Inertia

Numbness

Pessimistic Thoughts

Suicidal Thoughts

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SUB-ANALYSIS: REDUCED ADVERSE EVENTS FOR DROPS VS TABLETS

BRINTELLIX EXPERIENCE 18431N / SUB-ANALYSIS TABLETS VS. DROPS, ANALYSIS SET 20.01.2023, DATA ON FILE

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Adverse events for patients on drops (8.3%) were significantly lower than that for patients on tablets (30%)

Most relevant adverse events were nausea, dizziness and headache

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SUB-ANALYSIS: UP-TITRATION OF DOSE FASTER FOR DROPS VS TABLETS

BRINTELLIX EXPERIENCE 18431N / SUB-ANALYSIS TABLETS VS. DROPS, ANALYSIS SET 20.01.2023, DATA ON FILE

4.7%

13.7%

17.7%

22.2%

28.1%

31.6%

31.2%

26.7%

35.0%

42.9%

46.4%

51.8%

51.9%

57.1%

Patients on drops started with a lower dose, BUT, as early as day 8, dosage was up-titrated more quickly than patients on tablets.

By Day 15, an even higher proportion of patients were on the higher doses of drops, compared to those on tablets (ie. 35% vs 13.7%).

Reasons for faster dose up-titration: better tolerability of drops due to slow and steady increase in dosage

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SUB-ANALYSIS: GENERAL TREND TOWARDS ACCEPTANCE OF HIGHER DOSE FOR DROPS VS TABLETS

BRINTELLIX EXPERIENCE 18431N / SUB-ANALYSIS TABLETS VS DROPS, ANALYSIS SET 20.02.2023, DATA ON FILE

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At each follow–up time point, considerably higher percentage of patients were on the higher doses of >10-15mg (red) and >15mg (black) for drops compared to tablets.

Majority of patients on tablets remained in the lower dose of >5-10mg (blue).

Better tolerability of drops, lower number of adverse events.

4.7%

13.7%

17.7%

22.2%

28.1%

31.6%

31.2%

26.7%

35.0%

42.9%

46.4%

51.8%

51.9%

57.1%

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REASONS AND ADVANTAGES OF USING DROPS

Reduce Side Effects

Reduce Medication Withdrawal Symptoms/ Effects

Flexibility to Modulate/ Personalise Dosage (to achieve optimal treatment outcomes and build relationship with patients)

Empower Patient to Take Control of their disease

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REASONS AND ADVANTAGES OF USING DROPS

Close-Monitoring of Treatment Response

To Allow Gradual Medication - Switching (In or Out)

Eliminate Nocebo Effect

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CASE 1: A WOMAN WITH MARKED SENSITIVITY TO ADVERSE EFFECTS

Patient history:

67 years old female patient in her third depressive episode

First episode at the age of 23, after the end of a romantic relationship

History of marked sensitivity to the adverse effects of drugs

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DEPRESSIVE EPISODES: ROAD MAP

In the second episode (at the age of 42), good response with Fluoxetine, which since the beginning caused many adverse effects: strong rebound anxiety, tachycardia, nausea

Quickly suspended after 6 weeks due to side effects (tachycardia and akathisia)

Then euthymic for several years until the present episode, which has been going on for over a month, with melancholic features

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CLINICAL MANAGEMENT

Reluctant to go to the psychiatrist for fear of having to take a drug again

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Given the difficulties in the past with antidepressants and the negative feeling of the patient with regard with a possible new antidepressant, I decided to prescribe Vortioxetine ODS

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Starting with a dosage of 1 drop a day (after breakfast), to be increased day by day with an increasing rate of 1 drop per day

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Until the dosage of 20 mg per day

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OUTCOME

The patient reported some improvements, without reporting any side effect. This point was really appreciated by the patient, and it was a relevant aspect for the continuation of the treatment

In agreement with her, I decided to increase the dosage, at the same rhythm of one drop per day, reaching the target dosage of 20 mg per day (20 drops)

The improvements in the depressive tone was evident. No adverse event was reported

The patient is still on treatment. In agreement with her, I decided to reduce the dosage to 10 drops, as maintenance therapy.

2 weeks

1 month

3 months

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CASE 2: THE IMPORTANCE OF “MODULATION” IN A COMPLEX CASE OF MAJOR DEPRESSION

Patient history:

21 years old, student of political science, works as a painter in a Roman atelier

No previous psychiatric treatment, no psychiatric symptoms during adolescence

Family history of bipolar disorder (mother's sister)

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DEPRESSIVE EPISODES: ROAD MAP

  • He has been showing depressive symptoms for two months:
  • anhedonic features
  • phobic anxiety with social withdrawal
  • presence of subtle delusional thoughts concerning his health
  • During the first meeting he reported the idea that "his life was meaningless..." and that sometimes he had the feeling that "dying would be better than living such a difficult and painful life...".

..I don’t feel emotions..

..I cannot paint anymore..

..my body is deteriorating day by day....

..no one can help me..

..nothing can give me pleasure..

I don’t feel energy in my body

..I have thoracic pain..

..help..

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CLINICAL MANAGEMENT

I prescribed him Vortioxetine ODS (5 drops), Brexpiprazole 1 mg and Alprazolam 1 mg (twice a day)

After one week the patient reported a reduction in anxiety and rumination, with no improvement in depressive symptoms. No manic/hypomanic symptoms

Therefore, I decided to increase the dosage to 10 drops, with some improvement in mood after 1 week. Suicidal ideas were absent

I increased the dosage to 13 drops and the patient, after another week, reported marked improvement

I gradually prescribed alprazolam reduction, until discontinuation.

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OUTCOME

The patient is euthymic. However, he reported a slight reduction in sleep duration (from an average of 7 hours per night to 5/6 hours). I reduced the dosage of Vortioxetine ODS to 10, resulting in stabilization

I reduced the Vortioxetine ODS to 5 and discontinued the Brexpiprazole

The patient is euthymic with Vortioxetine ODS, 5 drops.

1 month

2 months

6 months

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CASE 3: A CROSS SWITCHING OF ANTIDEPRESSANTS

  • 41 years old woman

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  • Recurrent major depression and panic attacks

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  • For 5 years on Paroxetine 40 mg/day

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DEPRESSIVE EPISODES: ROAD MAP

Previously always treated with Paroxetine

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Due to a sharp drop in libido and emotional flattening…

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…several autonomous attempts to reduce Paroxetine, with the onset of depressive rebound, panic attacks and withdrawal symptoms.

“I live life as if

there were a screen”

“I no longer feel emotions”

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CLINICAL MANAGEMENT

I introduce Vortioxetine ODS: first 1 drop after breakfast, then, with a daily increase of one drop per day, I reach 20 drops per day.

At the same time, I carry on the gradual and cross reduction of Paroxetine in drops, with the same rhythm.

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OUTCOME

After 20 days the patient suspended Paroxetine and introduced 20 drops of Vortioxetine.

She reports an improvement in libido. No other adverse effects determined by vortioxetine or paroxetine withdrawal.

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Grazie!!!