East Asian Arch Psychiatry 2024;34:29-36 | https://doi.org/10.12809/eaap2353

REVIEW ARTICLE

Paul A Maguire, Tarun Bastiampillai, Stephen Allison, Fiona Wilkes, Jeffrey CL Looi

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Paul A Maguire, Academic Unit of Psychiatry and Addiction Medicine, Australian National University School of Medicine and Psychology, Canberra Hospital, Canberra, Australia; Consortium of Australian-Academic Psychiatrists for Independent Policy and Research Analysis (CAPIPRA), Canberra, Australia
Tarun Bastiampillai, Consortium of Australian-Academic Psychiatrists for Independent Policy and Research Analysis (CAPIPRA), Canberra, Australia; College of Medicine and Public Health, Flinders University, Adelaide, Australia; Department of Psychiatry, Monash University, Melbourne, Australia
Stephen Allison, Consortium of Australian-Academic Psychiatrists for Independent Policy and Research Analysis (CAPIPRA), Canberra, Australia; College of Medicine and Public Health, Flinders University, Adelaide, Australia
Fiona Wilkes, Academic Unit of Psychiatry and Addiction Medicine, Australian National University School of Medicine and Psychology, Canberra Hospital, Canberra, Australia; Consortium of Australian-Academic Psychiatrists for Independent Policy and Research Analysis (CAPIPRA), Canberra, Australia
Jeffrey CL Looi, Academic Unit of Psychiatry and Addiction Medicine, Australian National University School of Medicine and Psychology, Canberra Hospital, Canberra, Australia; Consortium of Australian-Academic Psychiatrists for Independent Policy and Research Analysis (CAPIPRA), Canberra, Australia

Address for correspondence: Dr Paul Maguire, Academic Unit of Psychiatry and Addiction Medicine, Australian National University School of Medicine and Psychology, Building 4, Level 2, Canberra Hospital, PO Box 11, Woden, Australian Capital Territory, 2605, Australia.
Email: paul.maguire@anu.edu.au or paul.maguire@act.gov.au

Submitted: 25 November 2023; Accepted: 15 April 2024

Introduction

Posttraumatic stress disorder (PTSD) is a serious and disabling psychiatric condition that may occur following exposure to actual or threatened death, serious injury or violence.^1,2 Characteristic symptom domains include hyperarousal (heightened fear, irritability, sleep disturbance), re-experiencing (flashbacks, nightmares and reliving), and avoidance/numbing (inability to experience positive emotions and a feeling of detachment from others).^3-5 PTSD is often associated with significant levels of distress, major psychiatric and drug and alcohol comorbidities, reduced quality of life, and increased risk of mortality.^6,7

Evidence-based interventions for the treatment of PTSD include psychological therapies (such as cognitive behavioural therapy, cognitive processing therapy, exposure therapy, and eye movement desensitisation and reprocessing) and pharmacotherapy (fluoxetine, paroxetine, sertraline, and venlafaxine).^2,4,8,9 There is moderate-to- high-strength evidence for a medium-to-large-magnitude benefit (ie, standardised mean difference of 0.5-0.9) for all of the above psychological interventions but only a small-to-moderate-magnitude benefit (ie, standardised mean difference of 0.2-0.50) for the medications.^4,8 Even though these pharmacotherapies have been shown to be statistically and clinically superior to placebo, and, as such, have been classified as evidence-based interventions, there are still many patients (especially those not suited to psychological therapy) who suffer from ongoing PTSD symptoms, reduced level of functioning, and substantial disability.^8-10 Challenges with implementation of, and adherence to, evidence-based interventions, and greater disease severity and extent of comorbidity, may account for some of the gap between results of randomised controlled trials (RCT) and real-world outcomes in observational studies. A relatively recent systematic review of the prevalence and longitudinal trajectories of PTSD has revealed that about 40% of people with PTSD have a chronic course.¹¹ In addition, a very recent meta-analysis has shown a 32% to 47% increased risk of mortality, compared with controls without PTSD.⁶ Therefore, effective novel interventions for PTSD are welcome.

Rivastigmine was discovered serendipitously as a possible augmentation treatment option for treatment- refractory PTSD in 2013, when a veteran from the Iran- Iraq war with PTSD was mistakenly given this medication, in addition to existing treatments, and showed marked clinical improvement in symptoms and quality of life, after 1 month of treatment.¹² Based on two further case studies, rivastigmine was proposed as an effective and safe add-on for the treatment of chronic PTSD.¹²

However, no systematic review has ever been performed evaluating add-on rivastigmine in the management of treatment-resistant PTSD. Therefore, the aims of this systematic review are to address these research questions: (1) What is the efficacy of rivastigmine as an augmentation medication for patients with treatment- resistant PTSD? (2) What dose of add-on rivastigmine is required for optimal treatment of PTSD? (3) Does the current level of evidence justify the clinical use of rivastigmine as an adjunctive treatment for PTSD?

Methods

Protocol and registration

We registered our systematic review with Prospero on 19 June 2023 (reference: CRD42023431518).

Databases and search strategy

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed in conducting this systematic review (Figure 1). A comprehensive search was performed on the databases Ovid MEDLINE, PubMed, CINAHL, and EMBASE. Search terms included ‘rivastigmine’ OR ‘Exelon’ OR ‘rivastigmine augmentation’ OR ‘Exelon augmentation’ AND ‘posttraumatic stress disorder*’ OR ‘post-traumatic stress disorder*’ OR ‘PTSD’ OR ‘combat disorder*’ OR ‘post-traumatic symptoms’. The asterisk specified plural forms of the relevant word. The reference lists of papers were manually searched to identify any further relevant articles.

Eligibility criteria

Articles were included if they reported at least one trial of rivastigmine for at least 1 month in patients ≥18 years of age who had been diagnosed with PTSD; participants were to have had active PTSD symptoms not fully relieved by their current treatment intervention. Although there was a preference for articles reporting baseline (ie, pre- rivastigmine treatment) and follow-up (ie, post-rivastigmine treatment) objective measures of PTSD-related symptoms with instruments with established psychometric validity and reliability such as the PTSD CheckList–Military Version (PCL-M), articles were also included if they reported the use of more general (and subjective) methods to assess efficacy such as the clinician-rated Clinical Global Impression scale. Articles were excluded if there was a primary diagnosis of a psychiatric disorder other than PTSD or if they were secondary studies reporting on primary studies.

Study selection

Titles and abstracts from the search were reviewed independently by two authors to determine whether they met the eligibility criteria. Disagreements were resolved by consensus, if necessary, involving a third author.

Data extraction

Relevant study data were extracted from identified papers by one author and confirmed by a second author. This information included author(s), year, country, study design, participant numbers and characteristics (if available), medication dosage, medication duration, and baseline and follow-up outcome measures. Clinical improvement in PTSD was assessed using PCL-M total score and subscale scores (hyperarousal, avoidant/numbing, and re- experiencing).

Quality assessment of included studies

The Quality Assessment Tool for Quantitative Studies was used to assess the quality of the RCT and the open trial. For the case reports, the Case Reports Guidelines checklist was used.

Results

As shown in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart (Figure 1), of 65 articles identified with our search strategy, eleven duplicates were removed and a further 50 articles were excluded due to not meeting eligibility criteria. Four papers were included in analysis, comprising one RCT,⁵ one non-controlled open trial,¹³ one case series (with three case reports),¹² and a paper with two case reports¹⁴ (Table 1).

Randomised placebo-controlled trial

In this RCT, the diagnosis of PTSD was determined by two national board-certified psychiatrists, based on the DSM- IV-TR criteria. Potential participants were screened for cognitive deficits using the Mini-Mental State Examination and were excluded if they scored <25. The 36 participants, all had ongoing combat-related PTSD symptoms, were administered a combination of a selective serotonin re- uptake inhibitor (SSRI), citalopram 40 mg/day, and sodium valproate (20 mg/kg/day) for 4 weeks and then reassessed. The rationale for this pre-treatment was that all patients had mood swings (including irritability) and hyperarousal symptoms, and therefore valproate was chosen for its properties as both a mood stabiliser and augmentation agent to the SSRI. Those patients who did not adequately respond to this medication regimen (<25% improvement in PCL-M scores) were then randomly assigned to one of three groups: (1) rivastigmine 6 mg/day, (2) placebo, or (3) treatment as usual. There were no statistically significant differences between the three groups for any PCL-M scores (Figure 2).

Non-controlled open trial

The open trial paper did not mention who made the diagnosis of PTSD but did indicate that the DSM-5 criteria were used. The average duration of symptoms prior to the trial was reported to be 9.8 years, and the participants recruited had not responded to treatment with either psychotherapy or at least two psychotropic medications. Unlike the RCT, this open trial did not reveal what measures and what thresholds were used to define a non-response to previous treatments. Principal presenting symptoms of most participants were intrusive memories, avoidant behaviour, and persistent anxiety or irritability (hyperarousal). Following treatment with rivastigmine, there were substantive improvements in the Clinical Global Impression score, participant-reported levels of overall benefit, and reduced frequency of specific PTSD symptom domains (Table 1).

Case reports

There were a total of five case reports: three described in a case series paper and two in a separate paper.

The three patients in the case series were all male veterans in the Iran-Iraq war (1980-1988), aged 45, 46, and 52 years, with severe, active PTSD symptoms in all domains (re-experiencing, avoidant/numbing, and hyperarousal). Despite treatment with multiple psychotropic medications (including antidepressants of both SSRIs and tricyclics, mood stabilisers, antipsychotic agents, benzodiazepines, and beta-blockers) starting at the onset of their PTSD, they experienced minimal recovery, with PCL-M total scores of 73, 71, and 67 prior to the add-on rivastigmine. Interestingly, the first patient was administered rivastigmine, 3 mg/day (in addition to citalopram, valproate, propranolol, and perphenazine) by error, following an incorrect reading of a prescription by the pharmacist. This mistake was discovered after 1 month, and the rivastigmine was continued for further 5 months because the patient reported dramatic improvement in PTSD symptoms and quality of life. The second patient, having heard about the first patient, requested that rivastigmine be added to his current treatment regimen, which consisted of nortriptyline, sertraline, perphenazine, and alprazolam. He had suffered a wide range of PTSD symptoms for 23 years. He also experienced reductions in PCL-M score after taking rivastigmine. The third patient experienced continuing long-term PTSD symptoms in all domains, despite previous trials of high doses of antidepressants (SSRIs and tricyclics), antipsychotics, benzodiazepines, and anticonvulsants. After addition of rivastigmine (dose not reported) to his concurrent treatment regimen of trimipramine, sertraline, perphenazine, clonazepam, and valproate, there were significant reductions in PCL-M scores. There were no significant adverse drug effects for any of the three patients. The Monthly Index of Medical Specialities recommends that the combination of a tricyclic antidepressant and an SSRI should be used with extreme caution and warns of severe, well-established potential drugs interactions including serotonin syndrome and tricyclic antidepressant toxicity (including confusion, sedation, delirium, and fatality). It seems possible that at least some of the symptoms experienced by patient 2 (extreme agitation, irritability, dysphoria, insomnia) may have been contributed to by the concomitant use of these antidepressants, although a clear temporal relationship is needed to assert this more confidently.

The final paper examined the effect of add-on rivastigmine on two ex-military patients (one male and one female) with PTSD, with measurements of pre- and post- PCL-M scores. Age was not reported for either patient. The first patient had spent 20 years in military service and subsequently joined the police force for 3 years. He presented with an 8-year history of PTSD symptoms and a recent suicide attempt. His presentation was complicated by alcohol dependence issues as he was consuming one 750 ml bottle of bourbon or 12 cans of beer a night. Commencement of rivastigmine was associated with significant improvement in PCL-M scores (Table 1). The second patient was a naval officer who was diagnosed with PTSD about a year after serving in a peacekeeper role in South Sudan. Her symptoms included severe panic attacks, distressing flashbacks, affect dysregulation (including terror and anger), and recently attempted suicide. Treatment had included trials of escitalopram, sertraline, and amitriptyline, all of which were unsuccessful. Although the patient reported some improvement with a trial of eye movement desensitisation and reprocessing, it appeared to be associated with increased levels of agitation and aggression and therefore was ceased. Rivastigmine was associated with significant improvements in PCL-M scores (Table 1).

Discussion

Rivastigmine has been proposed as effective and safe for the treatment of refractory PTSD.^12-14 However, this systematic review has found insufficient evidence supporting the use of rivastigmine for PTSD. The only RCT found no significant difference in health outcomes between the rivastigmine group and either the placebo or treatment as usual groups.⁵ The non-controlled open trial of 44 patients reported 81% improvement on Clinical Global Impression scores, but its methodological shortcomings provide limited information regarding the efficacy of add-on rivastigmine treatment.¹³ The five case studies, although promising in their results, do not constitute substantive support, and the reported improvement may have resulted from confounding factors.^12,14

The quality of the RCT and the open trial was assessed using the Quality Assessment Tool for Quantitative Studies (Table 2),^5,13 whereas the quality of the two case series was assessed using the Case Reports Guidelines checklist (Table 3).^12,14 Taken as a whole, the quality of the studies in this review was poor to moderate, with major limitations including small sample sizes, biased samples, failure to control for confounders, inadequate data collection methods, and suboptimal reporting of results. These shortcomings have negatively impacted on the ability to make robust conclusions about the efficacy of rivastigmine for the treatment of PTSD, making it unfeasible to generalise findings to the general/civilian population. In addition, restrictions in the rivastigmine dose range used do not allow a conclusion to be reached that doses higher than 6 mg/day are ineffective in the treatment of PTSD.

Our review also reveals that there is considerable variation in clinical presentations of PTSD including duration and severity of symptoms, level of functional impairment, and presence of comorbidity. These factors are likely to influence the magnitude of efficacy of any interventions including rivastigmine. This heterogeneity produces challenges in comparing studies with each other, as well as in assessing the efficacy of rivastigmine within a study.

Given that PTSD is a complex condition, the specific outcome measures selected are important and need to enable the researcher to gauge the impact on the sufferer’s life and sense of well-being. Therefore, although the PCL-M is a key and valuable assessment tool, additional outcome measures are needed to gain a broader assessment of the efficacy of any new treatment in terms of quality of life. Disappointingly, only one study included a quality-of-life measure in their methodology, but these results were not reported.⁵

Part of the evaluation of the possible efficacy of rivastigmine in the treatment of PTSD is to explore the benefits in different symptom domains. Two studies in this review (the RCT and the case series) reported the PCL-M subscale scores to enable examination of these symptom profiles post-treatment. Findings were different between the RCT and the case series. In the latter, avoidance, re- experiencing, and hyperarousal domains all improved, whereas in the former, avoidance and re-experiencing symptoms improved but not hyperarousal symptoms.

Specific limitations for the RCT and the open trial are provided in Table 4, using the Quality Assessment Tool for Quantitative Studies. Limitations for the case studies included missing key demographic and clinical data including patients’ age, rivastigmine dose, and the time frame of its use (when switching from 3 mg/day to 6 mg/day), and lack of precise description of symptoms including insufficient information on patient perspectives.

Although there is a putative pathophysiologic mechanism of improvement in PTSD with rivastigmine, based on enhancement of cognitive function through enhanced levels of rivastigmine, there is, unlike Alzheimer’s dementia, no clear evidence of a deficiency in this acetylcholine neurotransmitter in PTSD.¹⁵ However, some individuals with PTSD may be in the early stages of dementia or have mild cognitive impairment, which may not be detected in screening with a brief cognitive assessment. Therefore, consideration should be given to the use of comprehensive cognitive assessment such as the Addenbrookes Cognitive Examination,¹⁶ or neuropsychological examination performed by a neuropsychologist. Furthermore, some patients with combat- related PTSD may have suffered traumatic brain injuries, which may further complicate evaluation of cognitive loss and may or may not improve with rivastigmine, depending on the underlying neuropathology.¹⁷ In addition, as noted above, the DSM-5 diagnostic criteria for PTSD includes cognitive symptoms such as inability to recall trauma and concentration problems, which are assessed as part of scales used, such as the PCL-M.^1,18 It would be interesting to understand if there had been improvements in these specific domains of the PCL-M.

Further RCTs may help evaluate the potential usefulness of rivastigmine in treatment-refractory PTSD. Perhaps these could be preceded by smaller well-designed preliminary studies, administering higher rivastigmine dose ranges of up to 12 mg/day, to determine whether full-scale RCTs are indicated. All further studies would benefit from screening the sample population for co-existing cognitive deficits using appropriate neuropsychological testing, and controlling for potential confounders such as socioeconomic status, substance or alcohol use, medical and psychiatric comorbidities, level of social support, and concurrent medication use with rivastigmine. It would be useful to include civilian samples in addition to studies involving military and police. Other novel treatments for PTSD such as virtual reality therapy could also be explored.¹⁹

Conclusion

There is currently insufficient evidence to support rivastigmine augmentation in patients with treatment-

refractory PTSD in clinical practice. Accordingly, until such evidence becomes available, the treatment for PTSD should remain evidence-based pharmacotherapy and trauma- focused psychological therapies. Additional research is required to adequately evaluate the potential clinical efficacy of rivastigmine as an intervention for PTSD.

Contributors

PAM and JCLL designed the study and acquired and analysed the data. PAM drafted the manuscript. All authors critically revised the manuscript for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

All authors have disclosed no conflicts of interest.

Funding/support

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

All data generated or analysed during the present study are available from the corresponding author on reasonable request.

References

1. Weathers FW, Marx BP, Friedman MJ, Schnurr PP. Posttraumatic stress disorder in DSM-5: new criteria, new measures, and implications for assessment. Psychol Inj Law 2014;7:93-107. ^Crossref
2. Wallace D, Cooper J. Update on the management of post-traumatic stress disorder. Aust Prescr 2015;38:55-9. ^Crossref
3. Martin A, Kosari S, Peterson GM, Thomas J, Morris P, Naunton M. Pharmacological management of post-traumatic stress disorder and its associated nightmares: a survey of psychiatrists. J Clin Pharm Ther 2021;46:158-65. ^Crossref
4. Yan JZ, Liu JL, Li XZ, et al. Effectiveness, acceptability and safety of pharmaceutical management for combat-related PTSD in adults based on systematic review of twenty-two randomized controlled trials. Front Pharmacol 2022;12:805354. ^Crossref
5. Ardani AR, Hosseini G, Bordbar MRF, Talaei A, Toroghi HM. Effect of rivastigmine augmentation in treatment of male patients with combat-related chronic posttraumatic stress disorder: a randomized controlled trial. J Clin Psychopharmacol 2017;37:54-60. ^Crossref
6. Nilaweera D, Phyo AZZ, Teshale AB, et al. Lifetime posttraumatic stress disorder as a predictor of mortality: a systematic review and meta-analysis. BMC Psychiatry 2023;23:229. ^Crossref
7. Giesinger I, Li J, Takemoto E, Cone JE, Farfel MR, Brackbill RM. Association between posttraumatic stress disorder and mortality among responders and civilians following the September 11, 2001, disaster. JAMA Netw Open 2020;3:e1920476. ^Crossref
8. Courtois CA, Sonis J, Brown LS, et al. Clinical practice guideline for the treatment of posttraumatic stress disorder (PTSD) in adults. American Psychological Association. Accessed 25 November 2023. Available from: https://www.apa.org/ptsd-guideline/ptsd.pdf.
9. Martin A, Naunton M, Kosari S, Peterson G, Thomas J, Christenson JK. Treatment guidelines for PTSD: a systematic review. J Clin Med 2021;10:4175. ^Crossref
10. Coventry PA, Meader N, Melton H, et al. Psychological and pharmacological interventions for posttraumatic stress disorder and comorbid mental health problems following complex traumatic events: systematic review and component network meta-analysis. PLoS Med 2020;17:e1003262. ^Crossref
11. Santiago P, Ursano R, Gray C, et al. A systematic review of PTSD prevalence and trajectories in DSM-5 defined trauma exposed populations: intentional and non-intentional traumatic events. PLoS One 2013;8:e59236. ^Crossref
12. Fayyazi Bordbar MR, Talaei A. Rivastigmine as an effective add-on to standard treatment of veterans with chronic posttraumatic stress disorder: a case series. J Clin Psychopharmacol 2013;33:706-9. ^Crossref
13. Murray A, Wallace D, Nielssen O. Rivastigmine for treatment resistant post traumatic stress disorder. Aust N Z J Psychiatry 2017;51:946-7. ^Crossref
14. Rudzki S, Praet S. Five-year PTSD symptom remission in two patients following treatment with rivastigmine. Mil Med 2022:usac094. ^Crossref
15. Sherin JE, Nemeroff CB. Post-traumatic stress disorder: the neurobiological impact of psychological trauma. Dialogues Clin Neurosci 2011;13:263-78. ^Crossref
16. Mathuranath PS, Nestor PJ, Berrios GE, Rakowicz W, Hodges JR. A brief cognitive test battery to differentiate Alzheimer’s disease and frontotemporal dementia. Neurology 2000;55:1613-20. ^Crossref
17. Vasterling JJ, Jacob SN, Rasmusson A. Traumatic brain injury and posttraumatic stress disorder: conceptual, diagnostic, and therapeutic considerations in the context of co-occurrence. J Neuropsychiatry Clin Neurosci 2018;30:91-100. ^Crossref
18. Yarvis J, Yoon E, Ameuke M, Simien-Turner S, Landers G. Assessment of PTSD in older veterans: the Posttraumatic Stress Disorder Checklist: Military version (PCL-M). Adv Soc Work 2012;13:185-202. ^Crossref
19. Kothgassner OD, Goreis A, Kafka JX, Van Eickels RL, Plener PL, Felnhofer A. Virtual reality exposure therapy for posttraumatic stress disorder (PTSD): a meta-analysis. Eur J Psychotraumatol 2019;10:1654782. ^Crossref