Pharmacological interventions for persistent postural‐perceptual dizziness (PPPD)

Abstract Background Persistent postural‐perceptual dizziness (PPPD) is a chronic balance disorder, which is characterised by subjective unsteadiness or dizziness that is worse on standing and with visual stimulation. The condition was only recently defined and therefore the prevalence is currently unknown. However, it is likely to include a considerable number of people with chronic balance problems. The symptoms can be debilitating and have a profound impact on quality of life. At present, little is known about the optimal way to treat this condition. A variety of medications may be used, as well as other treatments, such as vestibular rehabilitation. Objectives To evaluate the benefits and harms of pharmacological interventions for persistent postural‐perceptual dizziness (PPPD). Search methods The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 21 November 2022. Selection criteria We included randomised controlled trials (RCTs) and quasi‐RCTs in adults with PPPD, which compared selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) with either placebo or no treatment. We excluded studies that did not use the Bárány Society criteria to diagnose PPPD and studies that followed up participants for less than three months. Data collection and analysis We used standard Cochrane methods. Our primary outcomes were: 1) improvement in vestibular symptoms (assessed as a dichotomous outcome ‐ improved or not improved), 2) change in vestibular symptoms (assessed as a continuous outcome, with a score on a numerical scale) and 3) serious adverse events. Our secondary outcomes were: 4) disease‐specific health‐related quality of life, 5) generic health‐related quality of life and 6) other adverse effects. We considered outcomes reported at three time points: 3 to < 6 months, 6 to ≤ 12 months and > 12 months. We planned to use GRADE to assess the certainty of evidence for each outcome. Main results We identified no studies that met our inclusion criteria. Authors' conclusions At present, there is no evidence from placebo‐controlled randomised trials regarding pharmacological treatments ‐ specifically SSRIs and SNRIs ‐ for PPPD. Consequently, there is great uncertainty over the use of these treatments for this condition. Further work is needed to establish whether any treatments are effective at improving the symptoms of PPPD, and whether their use is associated with any adverse effects.


A B S T R A C T Background
Persistent postural-perceptual dizziness (PPPD) is a chronic balance disorder, which is characterised by subjective unsteadiness or dizziness that is worse on standing and with visual stimulation.The condition was only recently defined and therefore the prevalence is currently unknown.However, it is likely to include a considerable number of people with chronic balance problems.The symptoms can be debilitating and have a profound impact on quality of life.At present, little is known about the optimal way to treat this condition.A variety of medications may be used, as well as other treatments, such as vestibular rehabilitation.

Objectives
To evaluate the benefits and harms of pharmacological interventions for persistent postural-perceptual dizziness (PPPD).

Search methods
The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov;ICTRP and additional sources for published and unpublished trials.The date of the search was 21 November 2022.

Selection criteria
We included randomised controlled trials (RCTs) and quasi-RCTs in adults with PPPD, which compared selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) with either placebo or no treatment.We excluded studies that did not use the Bárány Society criteria to diagnose PPPD and studies that followed up participants for less than three months.Outcomes

Risk with placebo Risk with SSRIs and SNRIs
Relative effect (95% CI) № of participants (studies) Certainty of the evidence (GRADE)

Comments
Improvement in vertigo at 6 to ≤ 12 months No studies assessed this outcome.
Change in vertigo at 6 to ≤ 12 months No studies assessed this outcome.

Serious adverse events
No studies assessed this outcome.

B A C K G R O U N D Description of the condition
Persistent postural-perceptual dizziness (PPPD) is a chronic balance disorder that is characterised by subjective unsteadiness or dizziness that is worse when standing up, moving around and in the presence of rich visual stimulation.Although the disorder was only defined in 2017, descriptions of individuals with the characteristic symptoms have been reported in the medical literature for many years (Staab 2017).The term itself has been used since at least 2013 (Staab 2020).In the past, individuals with these, or very similar, symptoms have been diagnosed with a variety of disorders, such as phobic postural vertigo, space-motion discomfort, visual vertigo or chronic subjective dizziness (Staab 2017).PPPD includes the core features of many of these disorders.
Criteria for diagnosis were established by expert consensus in 2017 and are based on symptoms alone.The presence of each of the following five features is required to make the diagnosis: • dizziness, unsteadiness or non-spinning vertigo, present on most days for at least three months; • the symptoms are exacerbated by an upright posture, motion or exposure to complex visual stimuli; • the disorder is triggered by an episode of unsteadiness, dizziness or vertigo -caused by another balance disorder, a neurological or medical disorder, or psychological distress; • symptoms must cause considerable distress to the su erer; • the symptoms should not be better accounted for by an alternative diagnosis.
As the diagnostic criteria were only recently established, accurate estimates of the prevalence and incidence of this newly characterised disorder are not yet available.However, a significant number of individuals with chronic balance problems, previously diagnosed with other conditions, may now be included within this diagnostic category.
The pathophysiological processes underlying PPPD are incompletely understood, although a model has been proposed to explain the likely mechanism (Staab 2020).This suggests that temporary changes in balance function caused by a specific event (such as an acute balance disorder, medical or psychological disturbance) become chronic, despite the resolution of the initial insult.Balance function appears to become more dependent on visual input, and individuals may be hypervigilant with regard to their own movement and balance.PPPD may reflect a maladaptation to an acute vestibular insult.
The impact of PPPD on the individual may be considerable, due to the chronic and persistent nature of the condition, and the consequences it has for day-to-day activities and quality of life.A small qualitative study recently identified three themes describing the impact of this disorder on individuals (Sezier 2019).These were a perception that their symptoms were not viewed as part of a valid or credible disorder, a change in their perceived self-identity since their symptoms started, and challenges in coping with the symptoms and changes in their lives.

Description of the intervention
In the absence of a good understanding of the pathophysiological mechanisms underlying PPPD, it is di icult to identify potential therapies based on any specific mechanisms.However, a variety of drugs and non-drug interventions have been used in people with balance disorders characterised by similar symptoms, and these are therefore considered possible therapeutic options in people with PPPD.
A small number of pharmacological interventions have been used for the treatment of PPPD (Popkirov 2018;Staab 2020).
Selective serotonin reuptake inhibitors (SSRIs) and serotoninnorepinephrine reuptake inhibitors (SNRIs) are, at present, the most commonly used medications for this disorder.Both are more widely used for depression and anxiety disorders.They are administered as oral tablets, usually titrating the dose up from a low starting level to reach the therapeutic range.Both classes of drug have a slow onset of action and, for depressive disorders, it may take several weeks before any benefit is seen.

How the intervention might work
Given the uncertainty in the pathogenesis of PPPD, at present no clear mechanism of action has been established for SSRIs and SNRIs.Possible modes of action may include altering hyperexcitability, or improving psychological symptoms (such as anxiety) that are present in many people with PPPD, or they may have direct e ects on the widespread balance network in the brain.
SSRIs act by preventing serotonin reabsorption by neurons, increasing serotonin levels in the brain.SNRIs have a similar mode of action, but inhibit the reuptake of both serotonin and norepinephrine.Serotonin receptors are found in the vestibular pathways within the brain (Balaban 2002), and there may consequently be direct actions of SSRIs and SNRIs on balance.
It is also recognised that many individuals with chronic dizziness have associated symptoms, such as anxiety, mood disturbance and panic attacks.The use of SSRIs and SNRIs in PPPD may help to alleviate some of these symptoms, with resulting improvement in quality of life.

Why it is important to do this review
Balance disorders can be di icult to diagnose and treat.There are few specific diagnostic tests, a variety of related disorders, and a limited number of interventions that are known to be e ective.
To determine which topics within this area should be addressed with new or updated systematic reviews, we conducted a scoping and prioritisation process, involving stakeholders (https:// ent.cochrane.org/balance-disorders-ent).PPPD was ranked as one of the highest priority topics during this process (along with vestibular migraine and Ménière's disease).
The impact on quality of life, and the absence of national or international management guidelines to recommend treatment strategies, make it important to review the evidence available to manage this condition.At present, there is no guidance available for healthcare professionals and patients to identify the possible benefits or harms of di erent treatment options.In this review, we aim to summarise the current evidence for pharmacological treatments for this condition; non-pharmacological therapies are addressed in another review (Webster 2022a).

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O B J E C T I V E S
To assess the benefits and harms of pharmacological interventions for persistent postural-perceptual dizziness (PPPD).

M E T H O D S
Criteria for considering studies for this review

Types of studies
We planned to include randomised controlled trials (RCTs) and quasi-randomised trials (where trials were designed as RCTs, but the sequence generation for allocation of treatment used methods such as alternate allocation, birth dates etc).We also intended to include cross-over trials and cluster-randomised trials, if we could correctly account for the correlation in the data.
For studies to obtain accurate estimates of the e ect of di erent interventions, we considered that follow-up of participants should be for at least three months, as the medications may take some time to take e ect, and this is a chronic illness, where short-term follow-up may not accurately represent the longer-term outcome for patients.Studies that followed up participants for less than three months were excluded from the review.

Types of participants
We included studies that recruited adult participants (aged 18 years or older) with a diagnosis of PPPD, according to the Bárány Society criteria (see Appendix 1).We excluded from the review studies that used alternative definitions of functional dizziness syndromes, such as chronic subjective dizziness (CSD), visual vertigo, spacemotion discomfort or phobic postural vertigo.Although we recognise that the symptoms of PPPD overlap considerably with some features of these disorders, we aimed to focus the results of the review so that they are directly relevant to those who are diagnosed with this (recently characterised) condition.
The main comparison was: • SSRIs and SNRIs versus placebo/no treatment.

Types of outcome measures
We planned to assess outcomes at the following time points: • 3 to < 6 months; • 6 to ≤ 12 months; • > 12 months.
The exception was for adverse event data, when we planned to use the longest time period of follow-up.
We searched the COMET database for existing core outcome sets of relevance to PPPD and vertigo, but were unable to find any published core outcome sets.We therefore conducted a survey of individuals with experience of (or an interest in) balance disorders to help identify outcomes that should be prioritised.This online survey was conducted with the support of the Ménière's Society and the Migraine Trust, and included 324 participants, who provided information regarding priority outcomes.The review author team used the results of this survey to inform the choice of outcome measures in this review.
We planned to analyse the following outcomes in the review, but we did not use them as a basis for including or excluding studies.

Primary outcomes
• Improvement in vestibular symptoms • Measured as a dichotomous outcome (improved/not improved), according to self-report, or according to a change of a specified score (as described by the study authors) on a rating scale.

• Change in vestibular symptoms
• Measured as a continuous outcome, to identify the extent of change in vestibular symptoms.• Serious adverse events • Including any event that caused death, was life-threatening, required hospitalisation, resulted in disability or permanent damage, or in congenital abnormality.Measured as the number of participants who experienced at least one serious adverse event during the follow-up period.

Search methods for identification of studies
The Cochrane ENT Information Specialist conducted systematic searches for randomised controlled trials and controlled clinical trials.There were no language or publication status restrictions.We only included studies that used the definition of PPPD that was defined in 2017 (Staab 2017), and first proposed in 2013 (Staab 2020).Therefore, we restricted some of the broader search terms to a year of publication from 2010 onwards.The date of the search was 21 November 2022.

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Electronic searches
The Information Specialist searched:

Searching other resources
We scanned the reference lists of identified publications for additional trials and contacted trial authors where necessary.In addition, the Information Specialist searched Ovid MEDLINE to retrieve existing systematic reviews relevant to this systematic review, so that we could scan their reference lists for additional trials.The Information Specialist also ran non-systematic searches of Google Scholar to retrieve grey literature and other sources of potential trials.
We did not perform a separate search for adverse e ects.We considered adverse e ects described in included studies only.

Selection of studies
At least two review authors or co-workers (of KG, TK, LS, KW) independently screened the titles and abstracts using Covidence (https://www.covidence.org), to identify studies that may be relevant for this review.Any discrepancies were resolved by consensus, or by retrieving the full text of the study for further assessment.
The full text of any study that appeared potentially relevant was obtained and again checked by two authors or co-workers (of KG, TK, LS, KW) independently to determine whether it met the inclusion criteria for the review.Any di erences were resolved by discussion and consensus, or through recourse to a third author if necessary.Studies that were retrieved in full text but subsequently deemed to be inappropriate for the review (according to the inclusion/exclusion criteria) are listed as excluded studies, according to the main reason for exclusion.We recorded the study selection process in su icient detail to complete a PRISMA flow diagram (Figure 1) and the Characteristics of included studies

Screening eligible studies for trustworthiness
We planned to assess all studies meeting our inclusion criteria for trustworthiness using a screening tool developed by Cochrane Pregnancy and Childbirth.This tool includes specified criteria to identify studies that are considered su iciently trustworthy to be included in the review (see Appendix 2).The process is outlined in Figure 2.

Figure 2. The Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool Data extraction and management
We planned that at least two review authors would independently extract outcome data from each study using a standardised data collection form, to include key characteristics of the studies.However, as no studies were identified for inclusion, this was not performed.

Assessment of risk of bias in included studies
We planned that two authors would undertake assessment of the risk of bias of any included studies independently, as guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011).

Measures of treatment e ect
We planned to summarise the e ects of dichotomous outcomes (e.g.serious adverse e ects) as risk ratios (RR) with 95% confidence intervals (CIs).For continuous outcomes, we would have expressed treatment e ects as a mean di erence (MD) with standard deviation (SD) or as a standardised mean di erence (SMD) if di erent scales had been used to measure the same outcome.

Unit of analysis issues
We did not encounter any unit of analysis issues, as we did not include any studies in this review.

Dealing with missing data
We did not identify any studies suitable for inclusion in this review, therefore we did not need to contact authors regarding missing data.

Assessment of heterogeneity
As no studies were included, we did not need to make an assessment of heterogeneity.

Assessment of reporting biases
See the protocol for more information on how we had planned to assess reporting bias (Webster 2022b).

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Subgroup analysis and investigation of heterogeneity
If statistical heterogeneity was identified, we planned to assess this considering the following subgroups: • Di erent types of medication, within a specific class.
• Di erent doses/frequency of administration.
• Use of concomitant treatment.

Sensitivity analysis
See the protocol for more information on the sensitivity analyses that we had planned to conduct (Webster 2022b).

Summary of findings and assessment of the certainty of the evidence
We planned to use the GRADE approach to rate the overall certainty of evidence using GRADEpro GDT (https://gradepro.org/) and the guidance in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2021).
We have prepared a summary of findings table for the main comparison: • SSRIs and SNRIs versus placebo/no treatment.
We included the primary outcomes in the summary of findings table and prioritised outcomes at the time point 6 to ≤ 12 months.

Results of the search
The searches in November 2022 retrieved a total of 1803 records.This reduced to 1233 a er the removal of duplicates.We screened the titles and abstracts of these 1233 records.We discarded 1232 records and assessed one full-text record, which was linked to one study.
We excluded one study (one record) with reasons recorded in the review (see Excluded studies).We did not identify any studies that were relevant for inclusion in this review.We also did not identify any ongoing studies for this review.
A flow chart of study retrieval and selection is provided in Figure 1.

Included studies
No studies were included in the review.

Excluded studies
We excluded one study from this review (Basta 2017).This was a trial of cinnarizine and dimenhydrinate for people undergoing vestibular rehabilitation.However, participants in this trial did not have PPPD -they were diagnosed with a variety of other balance disorders.

Risk of bias in included studies
No studies were included in the review.

E ects of interventions
See: Summary of findings 1 SSRIs and SNRIs compared to placebo or no treatment for PPPD No studies were included in the review.

Summary of main results
No studies were included in this review.

Overall completeness and applicability of evidence
At present, there is no evidence from placebo-controlled randomised controlled trials (RCTs) regarding the e icacy and harms of selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) for persistent postural-perceptual dizziness (PPPD).

Quality of the evidence
We planned to use GRADE to assess the certainty of the evidence for each of our outcomes.However, as we identified no studies for inclusion in this review we are not able to comment on the certainty of the evidence.

Potential biases in the review process
We adhered to our protocol during the review process.However, some decisions about relevant studies to include in this review may be subject to some debate.Firstly, we only included studies that compared SSRIs or SNRIs to a placebo or no treatment control group.This was because we did not consider there to be a 'gold standard' treatment available for PPPD.Therefore, to establish whether these interventions may be e ective, we needed to compare them to no treatment, or -ideally -a placebo.
Secondly, we did not include any studies that followed up participants for less than three months.This was because we considered that the e icacy of an intervention in a chronic condition, such as PPPD, could not be judged with very short follow-up.Even if an intervention is e ective at one month or two months, it does not mean that there will be persisting e icacy in the long term.However, despite this restriction, we did not identify any studies that were excluded on the basis of this criterion.Therefore, we think it unlikely that the review would be di erent if studies with shorter follow-up had been included.
Finally, in keeping with our protocol, we only included studies where participants had received a diagnosis of PPPD using the Bárány society criteria.This may have led to the omission of studies that predated these criteria and recruited participants with di erent -but related -diagnoses, such as chronic subjective dizziness or phobic postural vertigo.This could be regarded as a bias in the review process.Nonetheless, we considered it vital to focus the review on those people with a definitive diagnosis of PPPD, to assess the current evidence for this specific condition.

Agreements and disagreements with other studies or reviews
There are few published reviews that consider the e icacy and harms of interventions for PPPD.We did not identify any other systematic reviews that addressed this question.However, we note Cochrane Database of Systematic Reviews the findings of a recent narrative review on this topic, which also highlights the lack of RCTs in this field (Staab 2020).Results from a single RCT were included in this article (Yu 2018).However, this considered a non-pharmacological intervention (cognitive behavioural therapy) as an adjunct to sertraline treatment (an SSRI) for PPPD.

Implications for practice
At present there is no evidence regarding the e icacy or potential harms of the use of selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) for persistent postural-perceptual dizziness (PPPD).People with this condition, and healthcare professionals who work with them, should be aware of this uncertainty when deciding on interventions to use for their condition.
It should be noted that SSRIs and SNRIs are widely used for other conditions and have been associated with well-recognised side e ects, including psychological disturbance and gastrointestinal symptoms.The potential for these adverse e ects should be considered when weighing up the risks and benefits of treatment.

Implications for research
Further work is needed in this area to identify whether any interventions are e ective in the treatment of PPPD, and whether they are associated with any harms.The following conclusions relate to the evidence identified in this review, and a companion review on non-pharmacological interventions for PPPD: • Authors of future studies should ensure that the agreed diagnostic criteria for PPPD are used to identify study participants (Appendix 1).• There is currently no evidence from randomised controlled trials to support a 'gold standard' treatment for PPPD, although some interventions are in widespread use.Placebo-controlled trials are therefore vital to identify the potential e icacy of interventions for PPPD.Comparison with other interventions (of unknown e icacy) does not allow firm conclusions to be drawn.• PPPD is a chronic condition, with symptoms that can recur over months or years.This needs to be considered when designing clinical trials in this area, and determining the appropriate duration of follow-up.A number of studies were found in the literature that conducted short-term follow-up and assessed outcomes at four or eight weeks.We considered that it is not possible to draw conclusions about the e icacy of these interventions with such short follow-up.We would advocate that authors of future studies plan for a longer duration of follow-up to establish whether interventions have benefit for the long-term symptoms of this disorder.• As with other balance disorders, there should be agreement about which outcomes to measure in studies of PPPD, and how to measure them.There should also be agreement about what size of a di erence in symptoms would be meaningful and important to people with this condition.This can only be achieved through collaboration between people with PPPD, healthcare professionals and researchers, and development of a core outcome set would be advantageous.The development of the protocol (including the prioritisation of outcomes) for this review was informed by responses to a survey to encourage patient and public involvement in the review process.

A C K N O W L E D G E M E N T S
The development and distribution of this survey would not have been possible without the support of the Ménière's Society and the Migraine Trust, and the authors wish to thank them for their help.
The authors would like to thank Lee Yee Chong for her work on generic text that has been used and adapted (with permission) in the methods section of this review.We would also like to extend our thanks to Frances Kellie and Cochrane Pregnancy and Childbirth for their permission to use and reproduce the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool in this review.
Thank you to Laura Smith and Tomohiko Kamo for their assistance with si ing and study screening.
The authors are grateful to the external clinical peer reviewer of the protocol for this review, Patricia Grey for her consumer review of the protocol and Elizabeth Doney, Information Specialist with Cochrane Skin, for providing peer review comments on the dra search methods.Many thanks also to Mr Angus Waddell for peer review of the review.Our thanks also to Dr Roderick Venekamp for editorial sign-o of this review.
Finally, the authors wish to thank Jenny Bellorini (Managing Editor) and Samantha Cox (Information Specialist) with Cochrane ENT for their support with the development of this review.

Editorial and peer reviewer contributions
Cochrane ENT supported the authors in the development of this review.
The following people conducted the editorial process for this article: •

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confidence interval; PPPD: persistent postural-perceptual dizziness; SNRI: serotonin and norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor • the Cochrane ENT Trials Register (search via the Cochrane Register of Studies to 21 November 2022); • the Cochrane Central Register of Controlled Trials (CENTRAL) The Information Specialist modelled subject strategies for databases on the search strategy designed for CENTRAL, Ovid MEDLINE and Ovid Embase.Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Technical Supplement to Chapter 4 of the Cochrane Handbook for Systematic Reviews of Interventions version 6.1) (Lefebvre 2021). table.

Pharmacological interventions for persistent postural-perceptual dizziness (PPPD) (Review)
Copyright © 2023 The Authors.Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.
This project was supported by the National Institute for Health Research, via Cochrane Infrastructure, Cochrane Programme Grant or Cochrane Incentive funding to Cochrane ENT, as well as an Evidence Synthesis Programme grant (NIHR132217).The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Evidence Synthesis Programme, NIHR, NHS or the Department of Health.
Sign-o Editor (final editorial decision): Dr Roderick Venekamp, Julius Center for Health Sciences and Primary Care of the University Medical Centre Utrecht (Cochrane ENT Editor).• Managing Editor (selected peer reviewers, collated peer reviewer comments, provided editorial guidance to authors, edited the article): Jenny Bellorini, Cochrane ENT.• Copy Editor (copy editing and production): Jenny Bellorini, Cochrane ENT.• Peer reviewers: Mr Angus Waddell, Great Western Hospitals NHS Foundation Trust (clinical/content review), Dr Richard Rosenfeld, Cochrane ENT Editor (clinical/content review), Dr Jose Acuin, Cochrane ENT Editor (clinical/content review), clinical peer reviewer (protocol) (chose not to be publicly acknowledged) (clinical/content review), Patricia Grey (consumer review).