Background. Psychosis is a very common feature of Alzheimer’s disease (AD) that can emerge as the neurodegenerative disease progresses. The 5-hydroxytryptamine (5-HT2A) receptors are located postsynaptically to serotonergic neurons in the frontal cortex and mediate both excitatory and inhibitory neurotransmissions. However, the effectiveness and tolerance of negative modulators of 5-HT2A receptors in Alzheimer’s disease psychosis (ADP) are uncertain.
Objectives. To detect the negative modulators of the 5-HT2A receptor as a cure for ADP.
Materials and methods. The primary outcome indicator was the total Neuropsychiatric Inventory (NPI) score. Other prognostic indicators included Mini-Mental State Examination (MMSE), the Katz Index of Independence in Activities of Daily Living (KATZ), the discontinuation rate, and adverse events.
Results. Compared to placebo, 5-HT2A inverse agonists significantly reduced the NPI total score, the KATZ and the MMSE score. The pooled odds ratio (OR) was 1.64 (95% confidence interval (95% CI): 1.01–2.65) and the heterogeneity variance was estimated at Tau2 = 0.52 with an I2 value of 90%, a χ2 value of 111.31, p = 0.04, and z-value of 2.01. The risk difference (RD) between the 5-HT2A receptor negative modulators and placebo groups was 0.12 (95% CI: 0.00–0.24) and the heterogeneity was estimated at Tau2 = 0.03, χ2 value of 127.23, degrees of freedom (df) value of 9, I2 value of 93%, z-value of 1.92, and p-value of 0.01 (<0.05).
Conclusions. Our results suggest that negative modulators of 5-HT2A receptors are beneficial and well-tolerated in the treatment of ADP.
Key words: mirtazapine, trazodone, pimavanserin, Alzheimer’s disease psychosis (ADP), 5-hydroxytryptamine (5-HT2A) receptor
One of the most common illnesses affecting older people is dementia, which poses a significant challenge to global public healthcare. Nearly 47 million people worldwide were living with dementia in 2015 and, according to data from the World Alzheimer Report 2015, that number is expected to nearly double every 20 years.1, 2 A specific type of dementia, Alzheimer’s disease (AD), accounts for 50–70% of all dementia cases.3, 4 While AD is often thought of as a memory illness, behavioral and cognitive symptoms of dementia, including psychotic symptoms, are practically ubiquitous. During the course of the disease, more than half of affected people will suffer psychotic symptoms,5, 6 which frequently leads to the increased need of care, patient stress, institutionalization, and a reduction in quality of life.7, 8, 9, 10
The presence of delusions, delusional misidentification and hallucinations characterizes psychosis. Although this appears to be comparable to functional psychoses like schizophrenia, the psychotic experience of dementia patients is considerably distinct, manifesting largely as delusions and hallucinations. Approximately 35% of affected people have simple delusions; frequent symptoms include stealing, victimization, adultery, desertion, or the belief that a deceased relative is still alive.11, 12 Other misidentification-related delusions in AD include the conviction that one’s house is not their own, that a member of the family is somebody else, a copy or an impostor (Capgras delusion), or that some uknown person is residing in their home (phantom hostage delusion).13 Misinterpreting television images, mirror images or captured images for actual people or objects is a more typical symptom. With a median incidence of 23% in studies, illusions are one of the most prevalent psychotic symptoms in AD.14
Antipsychotics are perhaps the most commonly prescribed medicines for treating Alzheimer’s disease psychosis (ADP). However, their effectiveness is limited at best, and the risk of major side effects remains a concern.15 For example, risperidone and olanzapine, while used to reduce aggression in AD, have both been linked to significant detrimental cerebrovascular occurrences (such as stroke) and extrapyramidal adverse effects16; although quetiapine is frequently used, 2 meta-analyses showed no effect of quetiapine on neuropsychiatric symptoms (NPS).17, 18 Furthermore, all antipsychotics come with a warning label from the U.S. Food and Drug Administration (FDA) about increased mortality risk in Alzheimer’s patients (FDA, 2005).19 For all these reasons, treatment of ADP requires safer and more effective medication.
The ideal therapeutic approach requires a better understanding of the underlying neurobiological mechanisms. The pathological processes underlying AD are thought to be influenced by changes in the serotonergic neurotransmitter system. Studies showing deficiencies in serotonergic neurotransmission and a loss of dopamine-producing neurons and serotonin receptors in AD provide evidence for the role of serotonin in AD.20, 21, 22, 23 The 5-hydroxytryptaminergic system has long been implicated in the etiology of psychiatric disorders. Previous research suggests that excessive 5-hydroxytryptamine receptor 2A (5-HT2A receptor) activation may be disrupted, generating apical dendritic ion channel malfunction and dementia-related psychosis (DRP) clinical symptoms.24 Furthermore, a postmortem analysis of cortical nerve cells obtained from AD patients revealed that Aβ plaques disrupt peri-somatic contact of 5-HT2A receptor-expressing parvalbumin-positive interneurons with γ-aminobutyric acid (GABA)ergic pyramidal neurons,25 potentially promoting hyperactivity of neurons in contact with plaques.
Negative allosteric modulators of 5-HT2A receptors have been considered a potential treatment strategy for ADP, and these compounds, called negative allosteric modulators, have different inhibitory potencies ranging from almost neutral antagonists to full inverse agonists.26 Notably, 5-HT2A receptors also have a powerful effect on cognitive activity in AD and, as an antipsychotic, 5-HT2A receptor inverse agonists and antagonists improve cognitive impairment. Thus, suppressing 5-HT2A receptor activity with selective 5-HT2A inverse agonists or 5-HT2A receptor inverse agonists might potentially provide a novel treatment strategy for ADP. Through a meta-analysis of all relevant randomized controlled trials (RCTs), we examined whether a negative regulation of 5-HT2A receptors promotes ADP.
Differences in results may be explained by the small sample sizes. A meta-analysis is a statistical method that uses both weighted and combined statistics to compute a meaningful statistic in aggregate and then uses the combined estimated statistics to perform tests and assessments.27, 28 By combining the results of many comparable individual studies, meta-analysis increases the strength of the argument for preliminary conclusions and the strength of analytical assessment of effects. By meta-analyzing all relevant RCTs, we examined whether negative regulation of 5-HT2A receptors alleviates ADP.
The study aimed to perform the first meta-analysis of randomized, double-blind, placebo-controlled trials investigating negative modulators of the 5-HT2A receptor as a cure for ADP.
Materials and methods
This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.29 We conducted a systematic literature search based on the PICO strategy (Patients: AD; Intervention: 5-HT2A receptor negative modulator; Control: placebo; Outcome: Neuropsychiatric Inventory (NPI) total score (primary outcome)). Other prognostic indicators included Mini-Mental State Examination (MMSE), the Katz Index of Independence in Activities of Daily Living (KATZ), rate of discontinuation, and adverse events.
Criteria for inclusion, search strategy, data extraction, and outcome measurement
Blinded and unblinded RCTs of 5-HT2A receptor-negative modulators (including 5-HT2A receptor antagonists and 5-HT2A receptor inverse agonists) in patients with ADP were included. Such drug combinations are essential to advance the development of antineuropsychiatric drugs as they treat the disease while avoiding many of the side effects caused by nonselective receptor interactions. To determine all potentially relevant research, searched 5 different databases: PubMed, MEDLINE, Cochrane Library, Embase, and Web of Science. We considered all studies published up to 6 January 2022, without language restrictions. The following categories were included in the search: “serotonin 2A antagonist” OR “5-HT2A antagonist” OR “negative allosteric modulators of 5-HT2A receptors” OR “5-HT2A receptor antagonists” OR “5-HT2A receptor inverse agonists” OR “ritanserin” OR “ketanserin” OR “mirtazapine” OR “nefazodone” OR “cyproheptadine” OR “trazodone” OR “eplivanserin” OR “pimavanserin” OR “volinanserin”. For other applicable studies, we looked through the reference lists of pertinent papers.
The first 3 authors thoroughly examined the patient requirements in the reviewed studies. If the required data were missing, we contacted the author for more information. As a final step, the first 3 authors reviewed, extracted and entered the data into ReviewManager (RevMan) 5.3 (Cochrane, London, UK) independently. The methodological quality of the included articles was evaluated using Cochrane Risk Of Bias criteria (https://training.cochrane.org/online-learning/core-software/revman) We utilized the Cochrane statistical tool, Review Manager 5 (RevMan 2008; Cochrane), for quantitative tests.
Data synthesis and statistical analyses
Each reported outcome measure was assessed in the 10 included studies. The primary outcome indicator of efficacy is the change in ADP symptoms measured using the NPI.30 Secondary outcome indicators were changes in memory cognition and daily living ability measured using the MMSE31 and the KATZ.32 These outcomes were analyzed in terms of odds ratio (OR) and risk difference (RD).
RevMan v. 5.3 software was used for data analysis. Referring to the Cochrane Handbook for Systematic Evaluation 5.1.0,33 RD was employed as the impact indicator for dichotomous variables, and it served as the effect indicator for continuous variables. The effect indicators for the continuous variables were OR and RD. The estimates and 95% confidence intervals (95% CIs) are provided for each effect. Heterogeneity was determined with the χ2 test and the I2 test, and random effects model was used for the meta-analysis. The value of p < 0.05 was considered statistically significant.
General information on the inclusion of the study
The database search identified a total of 375 papers, of which 270 were duplicates. After reading the article titles and abstracts, 45 studies were excluded due to being non-RCTs, as well as to study population, interventions and outcome indicators not meeting the inclusion criteria; also, more duplicates were eliminated. During the full-text screening, we excluded a further 65 studies due to being review articles and to inconsistencies in the statistical methods used. Ultimately, 10 RCTs were analyzed to evaluate inverse activation of the 5-HT2A binding site in AD (Figure 1).34, 35, 36, 37, 38, 39, 40, 41, 42, 43
The characteristics of the trials included in this study are shown in Table 1. Ten RCTs included 1986 patients with ADP. Two studies lasted 6 weeks, 2 studies lasted 2 weeks, 2 studies lasted 12 weeks, and there was 1 study lasting for each of the following periods: 13, 8, 24, and 26 weeks. The number of patients examined in the analyzed studies varied from 24 to 219 in total. The patients were, on average, 71 years old. The pharmaceutical industry supported 4 studies. Two studies were conducted in Brazil, 3 in the USA and the remaining 5 in the UK. To assess the methodological quality of all studies, we used the Cochrane Risk of Bias criteria (Figure 2, Figure 3). All 10 studies used a randomization method and accounted for the specific method of randomization. The methodological quality of the included studies was high and the risk of bias was low with the Begg’s test p-value equal to 0.376 for the OR and 0.473 for the risk ratio (RR) (Figure 4).
Results of the meta-analysis
Among the 10 included studies, 2 assessed each of the outcomes, with the gain in psychiatric symptoms measured with the total NPI score as the main indicator of efficacy. The MMSE scale was used for the examination of intellectual status and the KATZ was used for the examination of daily functioning. The ORs and RRs for the 10 included studies are summarized in Table 2.
Results of the meta-analysis for primary and secondary outcomes
The current study has a pooled OR of 1.64 (95% CI: 1.01–2.65) with heterogeneity estimated at Tau2 = 0.52, χ2 value of 111.31, degrees of freedom (df) of 9, I2 of 92%, z-value of 2.01, and p-value of 0.04 (<0.05) (Figure 5). The pooled OR greater than 1 indicates that the positive outcomes are more likely and, therefore, that 5-HT2A receptor negative allosteric modulators are more effective in the treatment of ADP compared to placebo. Additionally, compared to placebo, 5-HT2A receptor antagonists significantly reduced the total NPI score, the MMSE score and the KATZ. The RD between the 5-HT2A receptor negative modulators and placebo groups was 0.12 (95% CI: 0.00–0.24) with heterogeneity of Tau2 = 0.03, χ2 value of 127.23, df value of 9, I2 value of 93%, z-value of 1.92, and p-value of 0.01 (<0.05). The pooled RD value of less than 1 indicates that an adverse outcome is less probable with 5-HT2A receptor negative allosteric modulators and that such modality is safe, when compared to placebo, for the treatment of ADP (Figure 6). There were almost no statistically significant differences between the groups in the occurrence of side effects such as agitation, falls, aggression, anemia, urinary tract infection, contusion, blood urea increased, peripheral edema, cellulitis, anxiety, behavioral and psychiatric symptoms, blood potassium increase, and gastrointestinal issues.
To the best of our knowledge, this is the first comprehensive meta-analysis of RCTs on the efficacy and tolerability of 5-HT2A receptor-negative modulators for the treatment of ADP. Of all the available 5-HT2A receptor-negative modulators, mirtazapine, trazodone, RG3487, donepezil, idalopirdine, masupirdine, and pimavanserin were studied in this meta-analysis. The main finding of our study was that the 5-HT2A receptor-negative modulators improved the overall NPI scores of ADP patients more than the placebo. There were notable variations in MMSE score, KATZ and incidence of adverse events between the 2 groups. Although the effect size of the benefit for psychiatric symptoms was small, overall, this study adds to the evidence base suggesting a potential benefit from this type of medication for people with ADP. Pimavanserin has a different mechanism of action and a different safety profile compared to the other 6 drugs, including a beneficial effect among AD patients who exhibited more severe psychotic symptoms and, thus, providing a potentially unique advantage in this population. However, future longer and larger trials are needed to study the efficacy and safety of this class of drugs in treatment of ADP.
The total NPI score was the primary outcome indicator of our study. Compared to the placebo, the improved total NPI score in the treatment group of ADP patients suggests that the negative allosteric modulators of 5-HT2A receptors studied here, namely mirtazapine, trazodone, RG3487, donepezil, idalopirdine, masupirdine, and pimavanserin, may alleviate NPS in AD patients. Their mechanism of action may lie in the fact that, first, 5-HT2A receptors play a role in the secretion of amyloid precursor proteins, which may promote the formation of amyloid plaques in AD, such that the negative regulation of this receptor could influence the etiological basis of AD.44, 45, 46, 47, 48 Second, several genetic polymorphisms associated with AD symptoms (such as hallucinations and delusions, which are the most common NPS) have been discovered that link the uptake of 5-HT2A receptors to the therapeutic management of psychiatric serotonin disorders.44 Finally, the cerebral availability of the serotonin precursor plasma tryptophan level decreases along with the activation of the immune system, which is believed to be upregulated in AD.49, 50 However, between the 2 types of negative modulators of 5-HT2A, the efficacy of mirtazapine for the treatment of ADP is likely to be marginal. Participants of the pimavanserin study had more severe psychotic symptoms and worse cognitive dysfunction than those in the mirtazapine study. This also suggests that the effect of pimavanserin was significantly higher in the prespecified subgroup with more severe psychotic symptoms.
More notably, the 2 RCTs reported in detail the effects of pimavanserin on NPI subdomain scores, although the reported subdomains were not the same. One study showed a beneficial effect of pimavanserin on irritability/instability in the NPI subdomain, while the other showed a significant effect of pimavanserin on alleviating hallucinations and delusions in the Neuropsychiatric Inventory – Nursing Home Version (NPI-NH) subdomain. Inverse agonists/antagonists of dopaminergic, muscarinic, histaminergic, and adrenergic receptors showed a minimal affinity for these receptors.51 The discovery that most antipsychotic drugs work by antagonizing the 5-HT2A receptor led to the development of pimavanserin.52 In the future, it is reasonable to assume that pimavanserin will be of greater value in the treatment of ADP. Furthermore, as the psychiatric symptomatology of ADP patients is diverse, future studies could examine the relationship between different symptomatology and drug efficacy, rather than just limiting it to a few symptomatologies of NPI.
Cognitive impairment is an important determinant of functional impairment in AD. In addition, several studies have shown that people with AD are more likely to experience NPS.53, 54 Cummings described the importance of appropriate interventions for psychiatric symptoms and hypothesized that reducing these symptoms might improve cognitive function in AD.55 The MMSE is one of the most common scales used for evaluating cognitive dysfunction56; thus, we used this tool to investigate the effects of negative allosteric modulators of 5-HT2A receptors on the cognitive function of patients with ADP. In our study, negative allosteric modulators of 5-HT2A receptors did not affect cognitive function in patients with ADP compared to placebo. Cognitive function was only assessed using MMSE in the current studies related to negative allosteric modulators of 5-HT2A receptors, so we were unable to analyze this variable more closely. In addition, baseline factors may have an impact on the effect size of these drugs in the AD population. Therefore, future studies might attempt to explore the response of subgroups of participants with different MMSE baseline scores to these types of drugs and refine the ideal target group for ADP treatment.
The psychotic symptoms associated with AD can lead to excessive functional dependence. However, there are cognitive and behavioral predictors of progression rates in AD.57, 58 Longitudinal studies have demonstrated that psychotic symptoms were associated with a decline in the ability to execute tasks of daily living.59, 60, 61, 62 Tran et al. showed that, over time, the higher the frequency of psychotic symptoms resulted in a more rapid decline of the activity of daily living (ADL).63, 64 In light of previous studies, we chose the KATZ as an assessment tool for ADL and wanted to explore whether changes in psychiatric symptoms caused by this drug might affect the presentation of ADL. However, the KATZ did not reveal any significant differences between the 2 groups, i.e., the effect of these drugs on improving psychiatric symptoms does not add to their benefit in treating AD patients’ ability to perform ADL. Although such medications do not improve ADL in patients with ADP, a better understanding of the variables associated with functional deterioration may guide the combination of medications or the development of new medications to promote independence and improve the quality of life in people with ADP and their caregivers.
Patients with AD should be cautious when taking antipsychotics, so we evaluated safety of this class of medication. Our findings showed no difference in the total number of adverse events between the 2 groups, with the most common adverse events being falls, urinary tract infections and agitation, suggesting that this medication may be a safe treatment for ADP. Additional studies are still needed to further elucidate the long-term safety of negative allosteric modulators of 5-HT2A receptors in patients with ADP and to assess tolerability related to aspects not included in this study.
To the best of our knowledge, this is the first complete meta-analysis of RCTs on the effect and tolerance of negative modulators of the 5-HT2A receptor for the treatment of ADP. We included 7 widely used receptor inverse agonists (mirtazapine, trazodone, RG3487, donepezil, idalopirdine, masupirdine, and pimavanserin). In addition to mirtazapine, trazodone and pimavanserin for patients with ADP, we discovered no RCTs on other 5-HT2A receptor-negative modulators. The primary finding of this study was that 5-HT2A receptor-negative modulators enhanced the total NPI score for individuals with AD much more than placebo. There was no significant difference in the MMSE score and the KATZ for patients compared to placebo, i.e., we did not observe a negative modulator effect on ADL and cognitive function. In addition, there were no differences in individual adverse events between the 5-HT2A receptor-negative modulators group and the placebo group. Our findings suggest that this new class of antipsychotics is effective in managing ADP and has an acceptable safety and tolerability profile.
Two RCTs reported the effects of pimavanserin on NPI subdomain scores, but the subdomains measured were not the same, so only descriptive analyses were presented. Pimavanserin treatment was shown to be beneficial for irritability/unsteadiness, but not for other NPI domains; another study showed significant efficacy for pimavanserin in improving the NPI-NH subdomains of hallucinations and delusions. Together, this evidence suggests that pimavanserin may have greater potential efficacy in improving psychiatric symptoms than other 5-HT2A receptor antagonists. In addition, the effects of other 5-HT2A receptor antagonists on the NPI subdomain will need to be reported in future trials. To better confirm the efficacy of 5-HT2A receptor antagonists on ADP, we suggest that future investigators rate NPS individually (e.g., the most common symptoms of hallucinations and delusions) or in multiple subdomains.
The limited number of included studies resulted in a funnel plot analysis being unable to detect publication bias. In addition, although the NPI-total effect is statistically robust, the lack of pooled analysis of sub-domain results may diminish its clinical significance. The lack of overall ADL and MMSE benefits may be the result of scores from different patients with different clinical courses in various trials. Finally, AD is a progressive neurodegenerative disease, which may also affect the results when all data are finally pooled.
Our findings show that negative allosteric modulators of 5-HT2A receptors (mirtazapine, trazodone, RG3487, donepezil, idalopirdine, masupirdine, and pimavanserin) have some benefits over placebo in the treatment of ADP. According to studies evaluating the drug, the most promising treatment for ADP seems to be pimavanserin. However, psychosis relief should be balanced against possible neurologic, metabolic and cardiovascular adverse effects. It is reasonable to consider negative allosteric modulators of 5-HT2A receptors as a possible treatment option given their safety and tolerability profiles. It is difficult, however, to draw any conclusions regarding the added value of using negative allosteric modulators of 5-HT2A receptors or other types of atypical antipsychotics. These drugs need to be evaluated for their efficacy and tolerability in ADP in greater detail. By doing so, we will be able to provide better guidance on how to use the medications in patients with APD.