Alpha-Stim AID for anxiety disorders

Evidence-based recommendations on AlphaStim AID for managing anxiety disorders.

# Recommendations
AlphaStim AID shows promise for managing anxiety disorders. However, there is not enough good-quality evidence to support the case for routine adoption.
Research is recommended to address uncertainties about AlphaStim AID's:
short- and long-term efficacy
position in the care pathway for managing anxiety disorders and
resource impact.This research should include:
a study to better understand how AlphaStim AID affects brain function in people with anxiety disorders
a randomised controlled trial comparing AlphaStim AID with individual cognitive behavioural therapy (CBT), medication or both.Find out details of the research recommended in section 4.11.
Why the committee made these recommendations
Treatment for anxiety disorders usually includes CBT, medication or both. AlphaStim AID uses an electric current intended to generate calming brain waves, which may relieve anxiety symptoms.
Clinical trial evidence shows that AlphaStim AID can relieve anxiety symptoms in people with anxiety disorders. But it is not clear how this happens and how much benefit people get. Also, the evidence is of low quality. How long any benefit lasts is unclear because most of the trials lasted for only 5 or 6 weeks. There is also no evidence comparing AlphaStim AID with individual CBT or medication.
The effect of adopting AlphaStim AID on costs and resources is unclear because its clinical effectiveness and its position in the care pathway are uncertain. AlphaStim AID is not recommended for routine adoption and further research is needed.# The technology

# Technology
AlphaStim AID is an electrotherapy device that uses a variable electric microcurrent to stimulate alpha wave activity. The current has a pulse repetition rate of 0.5 hertz, with a pattern of bipolar asymmetric rectangular waves which repeat at 10second intervals.
AlphaStim AID is compact, about the size of a mobile phone, and delivers an electric current through a pair of small clips attached to the ear lobes. The clips have removable soft pads that are moistened to ensure electricity conduction. The strength of the current can be adjusted. AlphaStim AID is recommended to be used for between 20 and 60 minutes every day, every other day or as needed to treat symptoms of anxiety. AlphaStim AID is battery powered and portable. The company has 7 previous versions of the AlphaStim AID device and states that all versions are based on the same mechanism of action.

# Innovative aspects
AlphaStim AID differs from other anxiety disorder treatments because it uses a patented electrical wave pattern that is transmitted to the brain to stimulate the production of alpha waves.

# Intended use
AlphaStim AID is intended to be used to treat anxiety, insomnia and depression. This guidance focuses on the use of AlphaStim AID for treating anxiety disorders. The device can be self-administered at home, or by a healthcare professional in a hospital or clinic. AlphaStim AID may affect the functioning of implanted cardiac pacemakers and defibrillators. The instructions for use note that people should not operate potentially dangerous machinery or vehicles during treatment, and sometimes for several hours after treatment. The safety of cranial electrotherapy has not been established during pregnancy. The device has a 5year warranty.

# Relevant pathway
NICE's guideline on generalised anxiety disorder and panic disorder in adults: management provides principles of care for people with generalised anxiety disorder. It recommends a steppedcare model to organise service provision and to help people with generalised anxiety disorder, their families, carers and practitioners choose the most effective intervention.
Improving Access to Psychological Therapies (IAPT) services provide evidence-based psychological therapies to people with anxiety disorders and depression. A clinical expert noted that IAPT teams are the standard structure of service provision for people with anxiety and depression in most regions of England. IAPT teams deliver the NICE-recommended stepped-care model for generalised anxiety disorder.
NICE's guideline on social anxiety disorder: recognition, assessment and treatment provides treatment principles for adults with social anxiety disorder. It recommends the use of individual cognitive behavioural therapy (CBT). If a person wants to have drug treatment, a selective serotonin reuptake inhibitor (escitalopram or sertraline) should be offered. For adults who decline CBT and drug treatment, short-term psychodynamic psychotherapy, that has been specifically developed to treat social anxiety disorder, should be considered.

# Costs
The cost of AlphaStim AID is 450 (excluding VAT) per device. The device can be reused by multiple people. A per-person treatment cost of 70 is used in the cost modelling, which is based on a treatment time of 10 weeks and includes 40 to cover other costs such as staff time, postage and consumables.For more details, see the Alpha-Stim website for Alpha-Stim AID for anxiety disorders.# Evidence

# Clinical evidence

## The clinical evidence comprises 6 studies, of which 3 are randomised controlled trials
Six studies provided evidence relevant to the decision problem in the scope, including 2 published randomised controlled trials, 1 unpublished randomised controlled trial and 3 non-comparative observational studies. The studies included between 12 and 197 people. Only 1 study used the current model of the device, the others used older models. One study was done in the UK.

## Evidence shows that using AlphaStim AID relieves anxiety symptoms
The 3 randomised controlled trials showed a statistically significant improvement in patient-reported anxiety scores with AlphaStim AID compared with drugs alone, a sham device or no treatment in people with anxiety disorders. The benefit of AlphaStim AID in relieving anxiety symptoms was also reported consistently in the observational studies.

## There is no evidence of the long-term effect of AlphaStim AID
The studies were of short duration (usually 5 to 6 weeks) with only 1 observational study reporting longerterm outcomes at 24 weeks.

## The published evidence on the effect of AlphaStim AID on quality of life is limited
Only 2 of the studies reported improvements in quality of life (Morriss et al. 2019, Lu and Hu 2014) using health questionnaire (EQ5D5L and WHOQOL BREF) scores. An improvement in quality of life was also reported with AlphaStim AID in a patient survey run by NICE's Public Involvement Programme. For details, see the assessment report overview in the supporting documents for this guidance.

## AlphaStim AID is considered a safe device
Adverse events reported with AlphaStim AID in 2 studies included mild headache, dizziness, nausea and feeling strange. Similar symptoms were reported by people who used AlphaStim AID in the patient survey that was done as part of this assessment. Additional symptoms reported in this survey included ear discomfort and worsening of anxiety symptoms. All reported adverse events were mild. The instructions for use note that prolonged electrotherapy stimulation treatment at currents higher than necessary may cause dizziness or nausea that can last for hours to days. The clinical experts did not identify any specific safety concerns with AlphaStim AID.

## Additional evidence on the mechanism of action of AlphaStim AID for treating anxiety disorders is uncertain
In response to consultation comments about the mechanism of action of AlphaStim AID, the external assessment centre (EAC) reviewed additional studies that were highlighted by the consultees. It concluded that 2 published studies (Kennerly 2004; Lande and Gragnani 2018), and 1 PhD thesis (Kennerly 2006) which reported electroencephalogram (EEG) parameters of brain activities after using the AlphaStim AID device, were potentially relevant. The EAC noted, however, that none of these studies examined the association between changes in brain wave activity and changes in anxiety symptoms. The EAC also reviewed a conference abstract and an unpublished single case report, which reported an increase in brain alpha waves and a reduction in perceived anxiety symptoms after using the AlphaStim AID device. But the EAC emphasised that these results should be treated with caution because of the small sample size and uncertainties around study details and the generalisability of the results.

## Further investigation of AlphaStim AID's mechanism of action is needed
Three clinical experts, including 1 expert with extensive expertise in interpreting EEG recordings, also reviewed the additional evidence and agreed with the EAC's conclusions. The expert with EEG expertise considered that further investigation, preferably in studies that include a sham control, is justified to improve the understanding of AlphaStim AID's mechanism of action.

# Cost evidence

## One UK study is included in the economic modelling
The company identified 1 UK study (Morriss et al. 2019). This reported the cost impact of AlphaStim AID as a treatment option for people with anxiety disorders who were waiting for individual cognitive behavioural therapy (CBT) delivered by Improving Access to Psychological Therapies (IAPT) services. No additional economic analyses were identified by the EAC.

## The company's IAPT model shows cost savings in treating anxiety disorders
The company developed a decision tree model with a time horizon of 6 months. The model compared the cost of using AlphaStim AID as an option for people waiting for individual CBT in IAPT services with that of individual CBT alone. The results showed that AlphaStim AID was cost saving by 817.68 per person.

## The EAC changes the company's IAPT model to reflect the evidence and expert opinion
The EAC agreed with many of the assumptions in the company's IAPT model but found some limitations. In the UK observational study, a significant proportion of people who were offered AlphaStim AID chose not to use it and preferred to wait for individual CBT (Morriss et al. 2019). The EAC therefore revised the model to reflect the reduced uptake of AlphaStim AID. The EAC also modified the structure of the model to better reflect the current care pathway as outlined by clinical experts. The EAC's base case included drug treatment as an option at the start of the pathway and for people whose anxiety symptoms did not respond to AlphaStim AID or individual CBT. The EAC excluded the second course of individual CBT for people whose anxiety symptoms did not respond to an initial course of treatment.

## The EAC's updated analysis suggests that cost saving is influenced by response rate and assumptions about the treatment pathway
The EAC's base case showed that using AlphaStim AID saved 80.79 per person compared with individual CBT. This was based on a 47.2% response rate with AlphaStim AID (Morriss et al. 2019) and a 54.2% response rate with individual CBT (Gyani et al. 2013). The reported response rate for AlphaStim AID included everyone who used it in the Morriss et al. study. However, many people may also have had individual CBT alongside or after AlphaStim AID. The reported response rates for treatment combinations were more uncertain and varied. For instance, the response rate was 65.0% in people using AlphaStim AID alone and 13.0% in people having AlphaStim AID followed by individual CBT (Morriss et al. 2019). The EAC explored the effect of different response rates and treatment regimens. For details, see the addendum to the EAC's assessment report in the supporting documents for this guidance.

## Additional analysis suggests cost savings but uncertainties remain
In response to committee, clinical expert and consultation comments, the EAC revised the IAPT cost model to more closely reflect the current IAPT pathway. Results from this model suggested that introducing AlphaStim AID to the current pathway could be cost saving and result in fewer people being discharged from IAPT to primary care for further treatment. However, because of the limited data available and uncertainties in the modelling, the EAC concluded that the cost impact of using AlphaStim AID in the current IAPT care pathway remained uncertain.

## A primary care cost model shows that using AlphaStim AID could have additional savings but does not reflect clinical practice
During consultation, the company submitted a new model, which included AlphaStim AID in primary care as a first-line treatment for anxiety. The model was based on an unpublished study in the NHS and the results showed a cost saving of 285.00 per person when AlphaStim AID was included in the care pathway. However, the EAC considered that the proposed model did not reflect clinical practice because it did not capture medication use, possible variations in treatment options and repeat visits to a GP or nurse.# Committee discussion

# Clinical-effectiveness overview

## A better understanding of how AlphaStim AID works in people with anxiety disorders is needed
The committee considered that AlphaStim AID's mode of action was uncertain although the clinical experts explained the physiological role of alpha brain waves in mediating feelings of calmness. The clinical experts and the external assessment centre (EAC) reviewed the evidence submitted at consultation. They concluded that there was no robust evidence showing the effect of regular use of AlphaStim AID on the brain waves of people with anxiety disorders. The committee considered that a clear understanding of the therapeutic effect of this technology is important. It proposed that further evidence is generated to investigate any acute or longer-term changes in brain activity after using AlphaStim AID in people with anxiety disorders. Potential studies could involve using a sham device as a control and recording brain activity, for example by electroencephalography or functional imaging.

## AlphaStim AID is a promising treatment option for managing anxiety disorders, but the evidence is weak
The randomised controlled trial evidence showed short-term relief of anxiety symptoms with AlphaStim AID in people with anxiety disorders. However, the committee noted that the quality of the evidence was low because of a high risk of bias. The committee was concerned about the possibility of a significant placebo effect with AlphaStim AID. But it also acknowledged that reducing anxiety symptoms was the most important outcome regardless of how this was achieved. The committee concluded that a well-planned and well-conducted trial is needed to be certain about AlphaStim AID's clinical benefit.

## Evidence on the long-term benefit of using AlphaStim AID is needed
The evidence consisted of relatively short-term studies, mostly with follow-up periods of 6 to 12 weeks. In 1 study follow up was 24 weeks. The clinical experts advised that anxiety disorders are long-term conditions and many people have relapses in symptoms. No convincing evidence was available on the longer-term benefits of AlphaStim AID and the committee concluded that further research was needed to explore this.

## More evidence is needed to assess the effect of AlphaStim AID compared with other options in the care pathway
The clinical experts explained that there are several different treatments offered to people with anxiety disorders in the NHS. The committee considered that Morriss et al. (2019) provided information about the use of AlphaStim AID in people waiting for individual cognitive behavioural therapy (CBT). But aside from this, there is a lack of evidence to support the use of AlphaStim AID at specific points in the pathway. Also, there is uncertainty about how the clinical effect of AlphaStim AID compares with other treatments. The committee noted, for example, that there was no evidence for the effect of AlphaStim AID compared with medication in people with anxiety disorders. It recognised that AlphaStim AID may not replace other options in the treatment pathway, but it could be an additional option (see section 4.7 and section 4.8). The committee proposed that further evidence would be helpful to understand AlphaStim AID's benefit compared with established treatments for anxiety disorders, such as individual CBT or medication, or both.

# Side effects and adverse events

## AlphaStim AID is a low-risk device with no serious side effects
The evidence suggested that adverse events with AlphaStim AID were mild. The clinical experts explained that people may have vertigo or dizziness when AlphaStim AID is first used, particularly at a high electric current, but these symptoms tend to lessen when the current is reduced. Data from the patient survey confirmed that the device is generally well tolerated. The committee concluded that people using AlphaStim AID have a low risk of side effects. Also, the device might be a treatment option for some people for whom conventional treatments are unsuitable or who would prefer to avoid them.

# NHS considerations overview

## Training and ongoing support is important for people using AlphaStim AID at home
The clinical experts advised that training on the correct use of AlphaStim AID is important and this is offered to people before treatment starts. This involves explaining technical issues such as ensuring correct connections and setting appropriate currents. The patient expert also noted that people may need ongoing support while using AlphaStim AID at home. The committee concluded that providing information and support was essential to ensure that the technology is used correctly.

## The position of AlphaStim AID in the treatment pathway is not clear
The clinical experts explained that because of the number of people with anxiety disorders there is huge pressure on individual CBT services. They also explained that individual CBT is not suitable for everyone and some people may have to wait a long time to have it. So, easy access to self-administered treatment such as AlphaStim AID that can be used at home is a potentially attractive option for people waiting for individual CBT. The committee also considered that a range of different options for anxiety disorders was needed in the NHS so that treatment can be tailored to the person's needs. The clinical experts explained that AlphaStim AID can be offered early in the care pathway (see section 4.8) and it may help people engage better with subsequent individual CBT if it is still needed. The clinical experts also suggested that AlphaStim AID may particularly benefit people who want to avoid taking medication or when medication is unsuitable for them. The committee understood the importance of choice in treating anxiety in primary care and that this technology could be used to complement existing treatments for anxiety disorders. It concluded that AlphaStim AID has the potential to be a useful addition to the care pathway if evidence showing its clinical benefits is generated (see sections 4.2 to 4.4).

## There is potential for AlphaStim AID to be used in primary care to help people manage anxiety disorders
The clinical experts explained about the potential role of AlphaStim AID in primary care, where there is an unmet clinical need for people with anxiety disorders. The committee noted that the EAC has reviewed the results of a study exploring the use of AlphaStim AID as a firstline treatment for anxiety in primary care. A clinical expert who is a GP described the use of AlphaStim AID within social prescribing in his practice. Initial results suggested that uptake of AlphaStim AID and feedback from people using it was good. The clinical experts advised that people who do not want to have medication or psychological therapy often prefer to use AlphaStim AID. The committee concluded that AlphaStim AID may fit better in primary care where a range of treatment options is needed and this should be explored in further studies.

# Cost modelling overview

## The EAC's updated IAPT model is acceptable but uncertainties remain
The committee considered that the Improving Access to Psychological Therapies (IAPT) model reflects current care but there was limited data available to populate the uptake and response rates in this complex pathway. The primary care model reflected an alternative position for the technology in the care pathway, but the committee again noted that limited data was available to populate the model. So, it was difficult to draw firm conclusions from either model about the cost benefits of using AlphaStim AID. The committee concluded that further clinical efficacy evidence was needed to accurately assess whether using AlphaStim AID alone or as an add-on treatment would lead to cost savings compared with standard care.

## Further information about resource use would be valuable
In the EAC's base-case analysis for the IAPT model, the main drivers in the cost model were the uptake rate and response rates for the different treatments. The clinical experts explained that the uptake rates were likely to vary across services and people's preferences. They considered that the uptake rate of 22% used in the EAC's model did not reflect the much higher rates found in their own clinical practice. The clinical experts also commented that people may stop treatment early with AlphaStim AID if their symptoms improved and this may have confounded the calculated response rates. The committee concluded that more robust data was needed to understand the potential resource impact of using AlphaStim AID in the NHS.

# Further research

## Further good-quality research is needed to address uncertainties about the clinical efficacy of AlphaStim AID
The committee noted the mostly positive patient experience described in the response to the patient survey and in patients' consultation comments. It considered that AlphaStim AID shows significant promise for managing anxiety disorders, but further studies are needed to address uncertainties about its clinical efficacy. A fundamental understanding of the effect of AlphaStim AID on brain function in people with anxiety disorders would be helpful. For example, from a study using electroencephalography or functional imaging in treatment and sham groups. The committee considered that a well-conducted randomised controlled trial should be done to evaluate the short- and long-term effects of AlphaStim AID compared with established treatment options such as medication and individual CBT. Such a study should include an assessment of patient-reported outcome measures and resource use to inform a future assessment of the cost consequence of using AlphaStim AID in the NHS.

## Collecting real-world data is encouraged
The committee considered that collecting realworld data on the use of AlphaStim AID would be helpful to understand issues in different clinical scenarios, such as:
people's treatment preferences
the uptake of the device and
the response rates and treatment completion rates.