Clinical trial NCT06805266: Vortioxetine for Depressive Symptoms and Freezing of Gait in Parkinson Disease
Official title: An Open Study to Evaluate the Efficacy of Vortioxetine on Freezing of Gait in Patients Affected by Parkinson Disease with Depressive Symptoms
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Parkinson Disease, Idiopathic
Freezing of Gait
Depression Not Otherwise Specified
Keywords: Parkinson Disease
freezing of gait
depression NOS
Lead sponsor: University of Salerno
Sponsor class: OTHER
First posted: 2025-02-03
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The present study involves patients with Parkinson Disease (PD) suffering from freezing of gait (FOG) and depressive symptoms. The main aim of the study is evaluating the efficacy of vortioxetine in reducing moderate/severe FOG not responsive to dopaminergic treatment in patients with PD with depressive symptoms.

Detailed description: Depression and anxiety are common in patients with Parkinson's disease (PD). In PD, several drugs, such as dopamine-agonists, inhibitors of serotonin uptake (SSRI), tricyclic antidepressants (TCAs) and norepinephrine uptake inhibitors (SNRI) are effective in treating depressive symptoms. Recently, a Delphi consensus has concluded that multimodal drugs, like vortioxetine, are good treatment options for depression in PD and an open-label prospective study has shown that the vortioxetine may improve depressive symptoms and cognition in PD patients with major depression Vortioxetine has different mechanisms of action; it is a serotonin transporter (SERT) inhibitor, an antagonist of 5-HT3, 5-HT7, 5-HTID, a partial agonist of 5-HT1B and a full agonist of 5-HT1A. Moreover, despite vortioxetine does not interact significantly with the norepinephrine transporters or dopamine transporters, it has been shown to increase extracellular levels of norepinephrine, dopamine, and non-monoamine neurotransmitters including acetylcholine. These effects are likely related to the interaction between vortioxetine and various serotonin receptors.

Depression and anxiety or panic attacks are commonly associated to freezing of gait (FOG) in PD. FOG is a disabling symptom of parkinsonian syndromes, whose pathophysiology is heterogeneous and partly unclear. The relationship between FOG and dopaminergic treatment is rather complex. Based on response to dopaminergic treatment, FOG may be responsive, unresponsive (or partially responsive) or induced by dopaminergic drugs. FOG, especially unresponsive FOG, is commonly associated with cognitive dysfunction, namely attentional-executive and visuospatial alterations in PD patients. Since FOG episodes might be related to the Off state and/or to dopaminergic underdosing in PD, the first treatment option should be the increase of dopaminergic drugs dose, when possible. FOG episodes that are less responsive or nonresponsive to dopaminergic treatment represent the greatest therapeutic challenge. Beyond dopaminergic pathway, non-dopaminergic networks, i.e. noradrenergic and cholinergic transmission, may play a role in the pathogenesis of FOG. We hypothesize that vortioxetine might be effective in treating FOG by enhancing both monoamine and non-monoamine neurotransmitters.

STUDY DESIGN Clinical evaluation will be performed during optimal on state of patients

VISIT 1:

1. Enrolment: Informed consent signature
2. Standardized gait analysis with wearable sensors:

   Patients will be videotaped and assessed with wearable sensors (Opal) while:

   A) Performing the Rating Instrument to Assess Festination and Freezing Gait in Parkinsonian Patients (RIAFFGPP) . In RIAFFGPP patients have to:

   i. Sit down on a chair set up in front of a door. ii. After 30 s, stand up and walk to a floor mark (40 x 40 cm) iii. Perform within the mark two 360° turns, clockwise (cw) and counter-clockwise (ccw) iiii. Open and walk through the door, turn outside, and come back to the chair

   B) Walking forward along a 10 m path during three conditions:

   i. self paced velocity ii. fastest as possible without running pace iii. self paced velocity with mental task (seven serial subtraction from 100 - counting aloud)
3. Clinical Global Impression scale (patient and clinician)
4. FOG Questionnaire referred to the on state
5. New freezing of gait questionnaire (NFOG-Q)
6. Falls Efficacy Scale
7. Cognitive function assessment:

   * MMSE
   * MoCA
   * FiPaT
   * Raven Progressive Matrices
   * The Benton Judgment of Line Orientation Test (JLOT)
   * Rey auditory 15-word learning test
   * Babcock story (episodic memory)
   * Rey Complex Figure (copy and recall)
   * Stroop test
   * Trial making test
   * Cancellation attentional matrices
   * Phonological verbal fluency
   * Semantic verbal fluency
   * Frontal Assessment Battery
   * Constructional Apraxia
   * SAND-Denomination
8. MDS-UPDRS
9. BDI-II
10. NPI
11. Apathy Scale
12. PDQ-8
13. Blood pressure, heart rate
14. Instruction to fill in a falls diary for the next 2 weeks

VISIT 2 (Start of treatment, after 14 days ± 3 days from Visit 1)

1. Enrolled patients will start vortioxetine:

   Vortioxetine Schedule:

   Vortioxetine 5 mg: once a day after lunch for one week, After one week, Vortioxetine 10 mg once a day
2. Instruction on filling in again a falls diary:

Four weeks after starting medication patients will fill in again a falls diary for the next 2 consecutive weeks

VISIT 3 (after 12 weeks ± 7 days from ):

1. Standardized gait analysis with wearable sensors (see visit 1)

   * RIAFFGPP
   * Walking forward along a 10 m path during three conditions
2. Clinical Global Impression scale (patient and clinician)
3. FOG Questionnaire
4. New freezing of gait questionnaire (NFOG-Q)
5. Falls Efficacy Scale
6. Cognitive function assessment (see visit 1)
7. MDS-UPDRS or
8. BDI-II
9. NPI
10. Apathy Scale
11. PDQ-8
12. Blood pressure, heart rate
13. Adverse events

Eligibility criteria: Inclusion Criteria:

1. Diagnosis of PD according to published criteria
2. Occurrence of depression according to Beck Depression Inventory II (score ≥ 15)
3. A score ≥ 2 on the freezing question #2.13 of part 2 of the MDS-UPDRS (moderate-severe FOG).
4. FOG not responsive to dopaminergic treatment.

Exclusion Criteria:

1. Treatment with IMAO-B (rasagiline, selegiline, safinamide) (to be included, IMAO-B need to be withdrawn for at least 15 days)
2. Concomitant treatment with other antidepressant drugs
3. Hepatic and renal insufficiency
4. Treatment with tramadol or triptans
5. Psychotic disorder
6. Dementia according to DSM-V

Primary outcomes:
measure: Change in the score of the Freezing Of Gait (FOG) Questionnaire referred to the "on state"
timeFrame: From enrollment to the end of treatment at 12 weeks
Secondary outcomes:
measure: Change on severity of FOG not responsive to dopaminergic treatment in patients with PD.
timeFrame: From enrollment to the end of treatment at 12 weeks
measure: Chenage on frequency of FOG not responsive to dopaminergic treatment in patients with PD.
timeFrame: From enrollment to the end of treatment at 12 weeks
Other outcomes:
Locations:
Study officials:
References:
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