Pharmacological interventions for persistent postural‐perceptual dizziness (PPPD)

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the benefits and harms of pharmacological interventions for persistent postural‐perceptual dizziness (PPPD). 

Background

Description of the condition

Persistent postural‐perceptual dizziness (PPPD) is a chronic balance disorder that is characterised by unsteadiness or dizziness, triggered by changes in position or 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 sufferer;

• 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 poorly 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 difficult to identify potential therapies based on any specific mechanisms. However, a variety of drugs and non‐drug interventions has 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. Selective serotonin reuptake inhibitors (SSRIs) and serotonin‐norepinephrine 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, improving psychological symptoms (such as anxiety) that are present in many people with PPPD, or they may have direct effects 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 difficult 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 effective. 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 different 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 2022). 

Objectives

To assess the benefits and harms of pharmacological interventions for persistent postural‐perceptual dizziness (PPPD). 

Methods

Criteria for considering studies for this review

Types of studies

We will 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). 

If cross‐over trials are identified then these will be included, providing the data are reported in an appropriate way to be included in the meta‐analysis. If cluster‐RCTS are identified then they will be eligible for inclusion, providing we can appropriately account for the clustering in the data analysis. 

We will include studies reported as full‐text, those published as conference abstracts only and unpublished data. 

For studies to obtain accurate estimates of the effect of different interventions, we consider that follow‐up of participants should be for at least three months, as the medications may take some time to take effect, 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 fewer than three months will be excluded from the review.

Types of participants

We will include studies that recruited adult participants (aged 18 years or older) with a diagnosis of PPPD, according to the Bárány Society criteria (see Appendix 1).

If there is uncertainty over the criteria used for the study, we may contact the study authors for further information. We will exclude from the review studies that used alternative definitions of functional dizziness syndromes, such as chronic subjective dizziness (CSD), visual vertigo, space‐motion discomfort or phobic postural vertigo. Although we recognise that the symptoms of PPPD overlap considerably with some features of these disorders, we hope to focus the results of the review so that they are directly relevant to those who are diagnosed with this (recently characterised) condition. 

Where studies have recruited participants with a variety of diagnoses (e.g. PPPD and other distinct conditions) we will only include the study if either

• the majority of participants (≥ 90%) have a diagnosis of PPPD; or

• subgroup data are available that will allow us to identify data relevant specifically to those with PPPD.

Types of interventions

We will include the following interventions:

• selective serotonin reuptake inhibitors (SSRIs);

• serotonin and norepinephrine reuptake inhibitors (SNRIs).

The main comparison will be:

• SSRIs and SNRIs versus placebo/no treatment.

Concurrent treatments

There will be no limits on the type of concurrent treatments used, providing these are used equally in each arm of the study. We will pool studies that include concurrent treatments with those where participants are not receiving concurrent treatment, but we will conduct subgroup analysis to determine whether the effect estimates may be different in those receiving additional treatment. 

Types of outcome measures

We will assess outcomes at the following time points:

• 3 to < 6 months;

• 6 to ≤ 12 months;

• > 12 months.

The exception will be for adverse event data, when we will 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. The results of this survey were used by the review author team to inform the choice of outcome measures in this review. 

We will analyse the following outcomes in the review, but we will 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 causes death, is life‐threatening, requires hospitalisation, results in disability or permanent damage, or in congenital abnormality. Measured as the number of participants who experience at least one serious adverse event during the follow‐up period.

Vestibular symptoms comprise a variety of different features, including frequency of episodes, duration of episodes and severity/intensity of the episodes. People may experience vertigo, dizziness or unsteadiness as part of this disorder. Where possible, we will include data for the vestibular symptoms outcomes that encompass all aspects (frequency, duration and severity/intensity of symptoms). 

Secondary outcomes

• Disease‐specific health‐related quality of life

  • Measured with the Dizziness Handicap Inventory (DHI, Jacobsen 1990), a validated measurement scale in widespread use. If data from the DHI are unavailable we will extract data from alternative validated measurement scales, according to the order of preference described in the list below (based on the validity of the scales for this outcome):

    • DHI short form (Tesio 1999);

    • DHI screening tool (Jacobsen 1998).

• Generic health‐related quality of life

  • Measured with a validated measurement tool that assesses global health‐related quality of life, such as the EQ‐5D‐3L (EuroQol 1990), EQ‐5D‐5L (Herdman 2011) or SF36 (Ware 1992).

• Other adverse effects

  • Measured as the number of participants who experience at least one episode of the specified adverse events during the follow‐up period, including the following specified adverse effects:

    • headache;

    • gastrointestinal disturbance;

    • sleep disturbance (e.g. somnolence or insomnia);

    • psychological disturbance (e.g. anxiety, depression, agitation);

    • cardiovascular disturbance (e.g. postural lightheadedness, palpitations);

    • sexual dysfunction.

Search methods for identification of studies

The Cochrane ENT Information Specialist will conduct systematic searches for randomised controlled trials and controlled clinical trials. There will be no language or publication status restrictions. We will only include studies that used the definition of PPPD that was defined in 2017 (Staab 2017), and first proposed in 2013 (Staab 2020). Therefore, we have restricted some of the broader search terms to a year of publication from 2010 onwards. We may contact original authors for clarification and further data if trial reports are unclear and we will arrange translations of papers where necessary.

Electronic searches

Published, unpublished and ongoing studies will be identified by searching the following databases from their inception:

• the Cochrane ENT Trials Register (search via the Cochrane Register of Studies to date);

• the Cochrane Central Register of Controlled Trials (CENTRAL) (search via the Cochrane Register of Studies to date);

• Ovid MEDLINE(R) Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) (1946 to date);

• Ovid Embase (1974 to date);

• Web of Knowledge, Web of Science (1945 to date);

• ClinicalTrials.gov, www.clinicaltrials.gov:

  • ClinicalTrials.gov (search via the Cochrane Register of Studies to date);

  • ClinicalTrials.gov (search via www.clinicaltrials.gov to date);

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP):

  • WHO ICTRP (search via the Cochrane Register of Studies to date);

  • WHO ICTRP (search via https://trialsearch.who.int to date).

The subject strategies for databases will be modelled on the draft search strategies in Appendix 2. Where appropriate, these will be 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).

Searching other resources

We will scan the reference lists of identified publications for additional trials and contact trial authors if necessary. In addition, the Information Specialist will search Ovid MEDLINE to retrieve existing systematic reviews relevant to this systematic review, so that we can scan their reference lists for additional trials.

We will not perform a separate search for adverse effects. We will consider adverse effects described in included studies only.

Data collection and analysis

Selection of studies

We will consider using Cochrane's Screen4Me workflow to help assess the search results, depending on the number of results retrieved from the database searches. Screen4Me comprises three components:

1. Known assessments – a service that matches records in the search results to records that have already been screened in Cochrane Crowd and been labelled as 'a RCT' or as 'not a RCT'.

2. The machine learning classifier (RCT model) (Wallace 2017), available in the Cochrane Register of Studies (CRS‐Web), which assigns a probability of being a true RCT (from 0 to 100) to each citation. For citations that are assigned a probability score below the cut‐point at a recall of 99% we will assume these to be non‐RCTs. For those that score on or above the cut‐point we will either manually dual screen these results or send them to Cochrane Crowd for screening.

3. Cochrane Crowd is Cochrane's citizen science platform where the Crowd help to identify and describe health evidence. For more information about Screen4Me and the evaluations that have been done, please go to the Screen4Me website on the Cochrane Information Specialist's portal and see Marshall 2018, McDonald 2017,  Noel‐Storr 2018 and Thomas 2017.

At least two review authors will independently screen the remaining titles and abstracts using Covidence (https://www.covidence.org), to identify studies which may be relevant for this review. Any discrepancies will be resolved by consensus, or by retrieving the full text of the study for further assessment. 

The full text of any study that may be relevant will be obtained and will again be checked by two authors independently to determine whether it meets the inclusion criteria for the review. Any differences will be resolved by discussion and consensus, or through recourse to a third author if necessary. 

Studies that are retrieved in full text but subsequently deemed to be inappropriate for the review (according to the inclusion/exclusion criteria) will be listed as excluded studies, according to the main reason for exclusion. 

The unit of interest for the review is the study, therefore we will group multiple papers or reports of a single study together under a single reference identification. We will record the study selection process in sufficient detail to complete a PRISMA flow diagram and the 'Characteristics of excluded studies' table. 

Screening eligible studies for trustworthiness

We will 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 sufficiently trustworthy to be included in the review (see Appendix 3). If any studies are assessed as being potentially 'high risk', we will attempt to contact the study authors to obtain further information or address any concerns. If we are unable to contact the authors, or there is persisting uncertainty about the study then it will not be included in the main analyses of this review. The reasons for concern, and communication with the authors, will be described in full. The data from any studies where there are persisting concerns will be included only with a sensitivity analysis (see Sensitivity analysis). The process is outlined in Figure 1. 

1.

The Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool

Data extraction and management

At least two review authors will independently extract outcome data from each study using a standardised data collection form. Where a study has more than one publication, we will retrieve all publications to ensure complete extraction of data. Any discrepancies in the data extracted by the two authors will be checked against the original reports, and differences will be resolved through discussion and consensus, with recourse to a third author where necessary. If required, we will contact the study authors for clarification.

We will include key characteristics of the studies, including (as a minimum) the following information:

• study design, duration of the study, number of study centres and location, study setting and dates of the study;

• information on the participants, including the number randomised, those lost to follow‐up or withdrawn, the number analysed, the age of participants, gender, diagnostic criteria used, inclusion and exclusion criteria for the individual studies;

• details of the intervention, comparator, and concomitant treatments or excluded medications;

• the outcomes specified and reported by the study authors, including the time points;

• funding for the study and any conflicts of interest for the study authors;

• information required to assess the risk of bias in the study and to enable GRADE assessment of the evidence.

Once the extracted data have been checked and any discrepancies have been resolved, a single author will transfer the information to Review Manager 5 (RevMan 2020). 

The primary effect of interest for this review will be the effect of treatment assignment (which reflects the outcomes of treatment for people who were assigned to the intervention) rather than a per protocol analysis (the outcomes of treatment only for those who completed the full course of treatment as planned). For the outcomes of interest in this review, we will extract the findings from the studies on an available case basis, i.e. all available data from all participants at each time point, based on the treatment to which they were randomised. This will be irrespective of compliance, or whether participants had received the intervention as planned.

In addition to extracting pre‐specified information about study characteristics and aspects of methodology relevant to risk of bias, we will extract the following summary statistics for each trial and outcome:

• For continuous data: the mean values, standard deviation and number of patients for each treatment group at the different time points for outcome measurement. Where change‐from‐baseline data are not available, we will extract the values for endpoint data instead. If values for the individual treatment groups are not reported, where possible we will extract summary statistics (e.g. mean difference) from the studies.

• For binary data: we will extract information on the number of participants experiencing an event, and the number of participants assessed at that time point. If values for the individual treatment groups are not reported, where possible we will extract summary statistics (e.g. risk ratio) from the studies.

• For ordinal scale data: if the data appear to be normally distributed, or if the analysis performed by the investigators indicates that parametric tests are appropriate, then we will treat the outcome measure as continuous data. Alternatively, if data are available, we may convert these to binary data for analysis.

• For time‐to‐event data: we do not anticipate identifying any time‐to‐event data for the outcomes specified in the review. If these are identified then, where possible, we will extract data on hazard ratios from individual studies. If these data are not provided then we will extract alternative measures of treatment effect, such as the observed and expected number of events in each group, a P value and the number of events in each arm, or data from a Kaplan Meier curve.

If necessary, we will convert data found in the studies to a format appropriate for meta‐analysis, according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2021). 

We have pre‐specified time points of interest for the outcomes in this review. Where studies report data at multiple time points, we will take the longest available follow‐up point within each of the specific time frames. For example, if a study reports an outcome at 12 weeks and 20 weeks of follow‐up then the 20‐week data will be included for the time point 3 to < 6 months.

Assessment of risk of bias in included studies

Two authors will undertake assessment of the risk of bias of the included studies independently, with the following taken into consideration, as guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011):

• sequence generation;

• allocation concealment;

• blinding;

• incomplete outcome data;

• selective outcome reporting; and

• other sources of bias.

We will use the Cochrane risk of bias tool (Handbook 2011), which involves describing each of these domains as reported in the trial and then assigning a judgement about the adequacy of each entry: 'low', 'high' or 'unclear' risk of bias.

Measures of treatment effect

We will summarise the effects of dichotomous outcomes (e.g. serious adverse effects) as risk ratios (RR) with 95% confidence intervals (CIs). For the key outcomes that we will present in the 'summary of findings' tables, we will also express the results as absolute numbers based on the pooled results and compared to the assumed risk. We may also calculate the number needed to treat to benefit (NNTB) using the pooled results. The assumed baseline risk is typically either (a) the median of the risks of the control groups in the included studies, this being used to represent a 'medium‐risk population' or, alternatively, (b) the average risk of the control groups in the included studies is used as the 'study population' (Handbook 2021). If a large number of studies are available, and where appropriate, we may also present additional data based on the assumed baseline risk in (c) a low‐risk population and (d) a high‐risk population.

For continuous outcomes, we will express treatment effects as a mean difference (MD) with standard deviation (SD) or as a standardised mean difference (SMD) if different scales have been used to measure the same outcome. We will enter data presented as a scale with a consistent direction of effect. We will provide a clinical interpretation of the SMD values using either Cohen's d or by conversion to a recognised scale if possible. 

Unit of analysis issues

We consider that PPPD can be regarded as a relatively stable condition, therefore cross‐over trials will be included in this review, if the data are reported in a way that allows for meta‐analysis. If cluster‐randomised trials are identified then we will ensure that analysis methods are used to account for clustering in the data (Handbook 2021). 

If we identify studies with three or more arms, we will ensure these are included to avoid double‐counting of any participants. If two arms relate to the same comparison (e.g. SSRI, SNRI and placebo) then we will include these data by pooling the relevant intervention arms, or by splitting the shared placebo group between the two intervention arms (according to methods in the Handbook 2021). 

Dealing with missing data

We will try to contact study authors via email whenever the outcome of interest is not reported, if the methods of the study suggest that the outcome had been measured. We will do the same if not all data required for meta‐analysis have been reported (for example, standard deviations), unless we are able to calculate them from other data reported by the study authors. 

Assessment of heterogeneity

We will assess clinical heterogeneity by examining the included studies for potential differences between them in the types of participants recruited, interventions or controls used and the outcomes measured. If necessary, we will provide a table to summarise the key similarities and differences between individual studies. 

We will use the I² statistic to quantify inconsistency among the studies in each analysis. We will also consider the P value from the Chi² test. If we identify substantial heterogeneity, we will report this and explore possible causes through pre‐specified subgroup analysis. 

Assessment of reporting biases

We will assess reporting bias as within‐study outcome reporting bias and between‐study publication bias.

Outcome reporting bias (within‐study reporting bias)

We will assess within‐study reporting bias by comparing the outcomes reported in the published report against the study protocol or trial registry, whenever this can be obtained. If the protocol or trial registry entry is not available, we will compare the outcomes reported to those listed in the methods section. If results are mentioned but not reported adequately in a way that allows analysis (e.g. the report only mentions whether the results were statistically significant or not), bias in a meta‐analysis is likely to occur. We will seek further information from the study authors. If no further information can be found, we will note this as being a 'high' risk of bias when the risk of bias tool is used. If there is insufficient information to judge the risk of bias we will note this as an 'unclear' risk of bias  (Handbook 2021). 

Publication bias (between‐study reporting bias)

We will assess funnel plots if sufficient studies (more than 10) are available for an outcome. If we observe asymmetry of the funnel plot, we will conduct more formal investigation using the methods proposed by Egger 1997. We will also report on whether there were any studies identified through trial registries and other sources (Searching other resources), with unpublished reports.

Data synthesis

Where possible and appropriate (if participants, interventions, comparisons and outcomes are sufficiently similar in the studies identified) we will conduct a quantitative synthesis of results. We will conduct all meta‐analyses using RevMan 2020. We anticipate that the underlying effect of the intervention may vary between studies, as there are likely to be differences between participants, settings and the interventions used for each study. We will therefore use a random‐effects method for meta‐analysis. We may explore whether the use of a fixed‐effect model substantially alters the effect estimates, especially if few studies are included in the meta‐analysis (see Sensitivity analysis). 

For dichotomous data, we plan to analyse treatment differences as a risk ratio (RR) calculated using the Mantel‐Haenszel methods.

For continuous outcomes, if all data are from the same scale, we will pool mean follow‐up values with change‐from‐baseline data and report this as a mean difference. If there is a need to report standardised mean differences then we will not pool endpoint and change‐from‐baseline data.

Improvement in vestibular symptoms may be assessed using a variety of methods, which consider different aspects of vestibular dysfunction. These include:

• frequency of episodes;

• duration of episodes;

• severity/intensity of episodes;

• a composite measure of all of these aspects:

  • for example, assessed with a global score ‐ such as "how troublesome are your balance symptoms?", rated on an ordinal scale.

For the outcomes "improvement in vestibular symptoms" and "change in vestibular symptoms", we will prioritise outcome measures that use a composite score ‐ encompassing aspects of the frequency, duration and severity/intensity of symptoms. Examples of this may include a global rating scale of the impact of vestibular symptoms (rated from 0 to 10, where 0 is defined as no symptoms, and 10 is defined as the most troublesome symptoms) or the vertigo/balance subscale of the Vertigo Symptom Scale (Yardley 1992), or Vertigo Symptom Scale Short Form (Yardley 1998). Where data from composite scores are not available, then we will include data on the frequency of vertigo episodes as an alternative measure.

Synthesis using other methods

If we are unable to pool numerical data in a meta‐analysis for one or more outcomes we will provide a synthesis of the results using alternative methods, following the guidance in chapter 12 of the Handbook 2021. The methods used will depend on the data available from the studies included in this review. We will provide descriptive statistics to summarise effect estimates if these are available from all studies. If effect estimates are not available, we may conduct vote counting, using the direction of effect. Where appropriate, we will present results using a visual display, such as an effect direction plot. 

Subgroup analysis and investigation of heterogeneity

If statistical heterogeneity is identified for any comparisons, we will assess this considering the following subgroups:

• Different types of medication, within a specific class.

  • For example, if we identify data on different types of SSRI or SNRI, we will pool these for the main analysis, but also assess the effect of individual drugs using subgroup analysis.

• Different doses/frequency of administration.

  • For example, if we identify data on SSRIs/SNRIs administered at high and low doses, we will pool these for the main analysis, but also assess the effect of different doses.

• Use of concomitant treatment.

  • We will consider studies where all participants were using concomitant treatment separately from those where the intervention was exclusively used.

Where possible, if data are reported separately for subgroups within an individual study, we will extract and use these data for subgroup analysis. However, we anticipate that most subgroup analysis will need to be conducted at the level of the individual study. 

We will use a formal test to assess whether subgroup differences may be present. However, these analyses are observational in nature, and therefore we will not draw conclusions about the relative effect of interventions for the different subgroups. 

Sensitivity analysis

If few studies are identified for meta‐analysis, the random‐effects model may provide an inaccurate measure of the between‐studies variance. Therefore, we may explore the impact of using a fixed‐effect model using a sensitivity analysis. 

If there is uncertainty over the diagnostic criteria used for participants in the studies (for example, if it is not clear whether participants were diagnosed using criteria that are analogous to the Bárány criteria) then we may also explore this by including/excluding those studies from the analysis. 

We will use the Cochrane Pregnancy and Childbirth Screening Tool to identify any studies where there are concerns over the data available. Any studies that are identified by this tool will be excluded from the main analyses in the review, but we will explore the impact of including the data from these studies through a sensitivity analysis. 

Summary of findings and assessment of the certainty of the evidence

Two independent authors will 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). Disagreements will be resolved through discussion and consensus, or with recourse to a third author if necessary. The certainty of evidence reflects the extent to which we are confident that an estimate of effect is correct and we will apply this in the interpretation of results. There are four possible ratings: high, moderate, low and very low. A rating of high certainty of evidence implies that we are confident in our estimate of effect and that further research is very unlikely to change our confidence in the estimate of effect. A rating of very low certainty implies that any estimate of effect obtained is very uncertain.

The GRADE approach rates evidence from RCTs that do not have serious limitations as high certainty. However, several factors can lead to the downgrading of the evidence to moderate, low or very low. The degree of downgrading is determined by the seriousness of these factors:

• study limitations (risk of bias);

• inconsistency;

• indirectness of evidence;

• imprecision; and

• publication bias.

We will justify all decisions to downgrade the certainty of the evidence using footnotes, and add comments to aid the interpretation of the findings, where necessary. 

We will prepare a summary of findings table for the main comparison:

• SSRIs and SNRIs versus placebo/no treatment.

We will include all primary outcomes in the summary of findings table. We will prioritise outcomes at the time point 6 to ≤ 12 months for presentation in the table. 

What's new

Date	Event	Description
8 April 2022	Amended	Amendment published to ensure figures display correctly.

History

Protocol first published: Issue 3, 2022

Appendices

Appendix 1. Diagnostic criteria for PPPD

The Bárány Society criteria for PPPD (Staab 2017):

1. One or more symptoms of dizziness, unsteadiness or non‐spinning vertigo, present on most days for three months or more:

   1. symptoms are persistent, but wax and wane;

   2. symptoms tend to increase as the day progresses, but may not be active throughout the entire day;

   3. momentary flares may occur spontaneously or with sudden movements.

2. Symptoms are present without specific provocation, but are exacerbated by:

   1. upright posture;

   2. active or passive motion without regard to direction or position; and

   3. exposure to moving visual stimuli or complex visual patterns, although these three features may not be equally provocative.

3. The disorder usually begins shortly after an event that causes acute vestibular symptoms or problems with balance, though less commonly it develops slowly. Precipitating events include acute, episodic or chronic vestibular syndromes, other neurologic or medical illness, and psychological distress.

   1. When triggered by an acute or episodic precipitant, symptoms typically settle into the pattern of criterion 1 as the precipitant resolves, but may occur intermittently at first, and then consolidate into a persistent course.

   2. When triggered by a chronic precipitant, symptoms may develop slowly and worsen gradually.

4. Symptoms cause significant distress or functional impairment.

5. Symptoms are not better attributed to another disease or disorder.

Appendix 2. Draft search strategies

CENTRAL (CRS)	MEDLINE (Ovid)	Embase (Ovid)
1 MESH DESCRIPTOR Dizziness EXPLODE ALL AND CENTRAL:TARGET 809 2 MESH DESCRIPTOR Vertigo AND CENTRAL:TARGET 509 3 MESH DESCRIPTOR Postural Balance AND CENTRAL:TARGET 0 4 MESH DESCRIPTOR Vestibular Diseases AND CENTRAL:TARGET 0 5 MESH DESCRIPTOR Motion perception EXPLODE ALL AND CENTRAL:TARGET 299 6 #1 OR #2 OR #3 OR #4 OR #5 1515 7 MESH DESCRIPTOR Chronic Disease EXPLODE ALL AND CENTRAL:TARGET 13660 8 (chronic or persistent or "long term" or longstanding):AB,TI,TO AND CENTRAL:TARGET 245806 9 #7 OR #8 247437 10 #6 AND #9 190 11 (chronic or persistent OR persisting or "long term" or longstanding) adj6 (dizziness OR dizzy OR vertigo OR vestibular):AB,TI,TO AND CENTRAL:TARGET 294 12 #10 OR #11 405 13 >2009:YR AND CENTRAL:TARGET 1020392 14 #12 AND #13 269 15 MESH DESCRIPTOR Perceptual Disorders EXPLODE ALL AND INSEGMENT 175 16 #6 AND #15 3 17 (persistent adj3 (perceptual or postural) adj3 (dizziness or vertigo)):AB,EH,KW,KY,MC,MH,TI,TO  AND CENTRAL:TARGET 12 18 (PPPD AND (dizziness or vertigo or vestibular)):AB,EH,KW,KY,MC,MH,TI,TO  AND CENTRAL:TARGET 11 19 #14 OR #16 OR #17 OR #18 273	MEDLINE (Ovid MEDLINE® Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE® Daily and Ovid MEDLINE®) 1946 to present   1 exp Dizziness/ 5763 2 Vertigo/ 10478 3 Postural Balance/ 25602 4 Vestibular Diseases/ 4511 5 exp Motion perception/ 16966 6 1 or 2 or 3 or 4 or 5 59217 7 exp Chronic Disease/ 271574 8 6 and 7 847 9 ((persistent or chronic or persisting or "long term" or longstanding) adj6 (dizziness or dizzy or vertigo or vestibular)).ab,ti. 1765 10 8 or 9 2439 11 (201* or 202*).yr. 13228363 12 10 and 11 1383 13 Perceptual Disorders/ 6739 14 13 and 10 11 15 (persistent adj3 (perceptual or postural) adj3 (dizziness or vertigo)).ab,ti. 102 16 (PPPD and (dizziness or vertigo or vestibular)).ab,ti. 75 17 12 or 14 or 15 or 16 1389 18 randomized controlled trial.pt. 545668 19 controlled clinical trial.pt. 94445 20 randomized.ab. 536242 21 placebo.ab. 222027 22 drug therapy.fs. 2382579 23 randomly.ab. 367234 24 trial.ab. 570881 25 groups.ab. 2255489 26 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 5137324 27 exp animals/ not humans.sh. 4894687 28 26 not 27 4469024 29 17 and 28 494	Embase 1974 to present   1 exp dizziness/ 84247 2 vertigo/ 47669 3 body equilibrium/ 20518 4 vestibular disorder/ 9404 5 exp movement perception/ 13785 6 1 or 2 or 3 or 4 or 5 164913 7 exp chronic disease/ 190351 8 6 and 7 1397 9 ((persistent or chronic or persisting or longstanding or "long term") adj6 (dizziness or dizzy or vertigo or vestibular)).ab,ti. 2406 10 8 or 9 3628 11 (201* or 202*).yr. 17776219 12 10 and 11 2234 13 exp perception disorder/ 35625 14 10 and 13 45 15 (persistent adj3 (perceptual or postural) adj3 (dizziness or vertigo)).ab,ti. 132 16 (PPPD and (dizziness or vertigo or vestibular)).ab,ti. 101 17 12 or 14 or 15 or 16 2248 18 Randomized controlled trial/ 678551 19 Controlled clinical study/ 464183 20 Random$.ti,ab. 1711730 21 randomization/ 91931 22 intermethod comparison/ 275752 23 placebo.ti,ab. 330279 24 (compare or compared or comparison).ti. 547713 25 ((evaluated or evaluate or evaluating or assessed or assess) and (compare or compared or comparing or comparison)).ab. 2377142 26 (open adj label).ti,ab. 91422 27 ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab. 249007 28 double blind procedure/ 188384 29 parallel group$1.ti,ab. 28187 30 (crossover or cross over).ti,ab. 112909 31 ((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab. 364054 32 (assigned or allocated).ti,ab. 429177 33 (controlled adj7 (study or design or trial)).ti,ab. 389388 34 (volunteer or volunteers).ti,ab. 261134 35 human experiment/ 555942 36 trial.ti. 340283 37 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 5534662 38 (random$ adj sampl$ adj7 ("cross section$" or questionnaire$1 or survey$ or database$1)).ti,ab. 12284 39 comparative study/ or controlled study/ 9044969 40 randomi?ed controlled.ti,ab. 326332 41 randomly assigned.ti,ab. 144742 42 39 or 40 or 41 9230030 43 38 not 42 8726 44 Cross‐sectional study/ 437766 45 randomized controlled trial/ or controlled clinical study/ or controlled study/ 8500635 46 (randomi?ed controlled or control group$1).ti,ab. 993836 47 45 or 46 8866090 48 44 not 47 284171 49 (((case adj control$) and random$) not randomi?ed controlled).ti,ab. 18978 50 (Systematic review not (trial or study)).ti. 187767 51 (nonrandom$ not random$).ti,ab. 17282 52 "Random field$".ti,ab. 2590 53 (random cluster adj3 sampl$).ti,ab. 1386 54 (review.ab. and review.pt.) not trial.ti. 929038 55 "we searched".ab. 62552 56 review.ti. or review.pt. 3133557 57 55 and 56 38528 58 "update review".ab. 119 59 (databases adj4 searched).ab. 45639 60 (rat or rats or mouse or mice or swine or porcine or murine or sheep or lambs or pigs or piglets or rabbit or rabbits or cat or cats or dog or dogs or cattle or bovine or monkey or monkeys or trout or marmoset$1).ti. and animal experiment/ 1123962 61 43 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 57 or 58 or 59 1388815 62 37 not 61 5249339 63 17 and 62 551

Appendix 3. Trustworthiness Screening Tool

This screening tool has been developed by Cochrane Pregnancy and Childbirth. It includes a set of predefined criteria to select studies that, based on available information, are deemed to be sufficiently trustworthy to be included in the analysis. These criteria are:

Research governance

• Are there any retraction notices or expressions of concern listed on the Retraction Watch Database relating to this study?

• Was the study prospectively registered (for those studies published after 2010)? If not, was there a plausible reason?

• When requested, did the trial authors provide/share the protocol and/or ethics approval letter?

• Did the trial authors engage in communication with the Cochrane Review authors within the agreed timelines?

• Did the trial authors provide IPD data upon request? If not, was there a plausible reason?

Baseline characteristics

• Is the study free from characteristics of the study participants that appear too similar (e.g. distribution of the mean (SD) excessively narrow or excessively wide, as noted by Carlisle 2017)?

Feasibility

• Is the study free from characteristics that could be implausible? (e.g. large numbers of women with a rare condition (such as severe cholestasis in pregnancy) recruited within 12 months);

• In cases with (close to) zero losses to follow‐up, is there a plausible explanation?

Results

• Is the study free from results that could be implausible? (e.g. massive risk reduction for main outcomes with small sample size)?

• Do the numbers randomised to each group suggest that adequate randomisation methods were used (e.g. is the study free from issues such as unexpectedly even numbers of women ‘randomised’ including a mismatch between the numbers and the methods, if the authors say ‘no blocking was used’ but still end up with equal numbers, or if the authors say they used ‘blocks of 4’ but the final numbers differ by 6)?

Studies assessed as being potentially ‘high risk’ will be not be included in the review. Where a study is classified as ‘high risk’ for one or more of the above criteria we will attempt to contact the study authors to address any possible lack of information/concerns. If adequate information remains unavailable, the study will remain in ‘awaiting classification’ and the reasons and communications with the author (or lack of) described in detail.

The process is described in full in Figure 1.

Contributions of authors

Katie Webster: scoped, designed and drafted the protocol with the help of the other authors. 

Natasha A Harrington‐Benton: patient/public guidance at all stages of protocol development, commented on and edited the draft protocol, and agreed the final version.

Owen Judd: clinical guidance at all stages of protocol development, commented on and edited the draft protocol, and agreed the final version.

Diego Kaski: clinical guidance at all stages of protocol development, commented on and edited the draft protocol, and agreed the final version.

Otto R Maarsingh: clinical guidance at all stages of protocol development, commented on and edited the draft protocol, and agreed the final version.

Samuel MacKeith: clinical guidance at all stages of protocol development, commented on and edited the draft protocol, and agreed the final version.

Jaydip Ray: clinical guidance at all stages of protocol development, commented on and edited the draft protocol, and agreed the final version.

Vincent A Van Vugt: clinical guidance at all stages of protocol development, commented on and edited the draft protocol, and agreed the final version.

Martin J Burton: clinical guidance at all stages of protocol development, commented on and edited the draft protocol, and agreed the final version. 

Sources of support

Internal sources

• No sources of support provided

External sources

• National Institute for Health Research, UK

  Infrastructure funding for Cochrane ENT

• National Institute for Health Research, UK

  This project is funded by the National Institute for Health Research (NIHR) Evidence Synthesis Programme (NIHR132217). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Declarations of interest

Katie Webster: none known.

Natasha A Harrington‐Benton: Natasha Harrington‐Benton is the Director of the Ménière’s Society, a national charity supporting people with vestibular conditions. The Ménière’s Society supports research in various ways, including distributing surveys and/or providing grant funding for projects studying vestibular conditions. Some of the studies they have previously funded may be included in the review. They do not carry out the research themselves and are not directly involved in projects.

Owen Judd: none known.

Diego Kaski: none known.

Otto R Maarsingh: none known.

Samuel MacKeith: Samuel MacKeith is the Assistant Co‐ordinating Editor of Cochrane ENT, but had no role in the editorial process for this protocol.

Jaydip Ray: none known.

Vincent A Van Vugt: none known.

Martin J Burton: Martin Burton undertook private practice until March 2020 and saw some patients with PPPD. He is the Co‐ordinating Editor of Cochrane ENT, but had no role in the editorial process for this protocol.

Edited (no change to conclusions)