Oxytocin for frontotemporal dementia: a systematic review

Abstract

Background:

The aim of this systematic review is to identify published randomized controlled trials (RCTs) that evaluated the use of oxytocin in individuals with frontotemporal dementia (FTD).

Methods:

A literature search was conducted of PubMed, MEDLINE, EMBASE, PsycINFO and Cochrane collaboration databases for RCTs in any language that evaluated the use of oxytocin in individuals with FTD. Bibliographic databases of published articles were also searched for additional studies.

Results:

A total of two RCTs that evaluated the use of oxytocin in individuals with FTD were identified. In one study, the use of oxytocin in individuals with FTD produced a reduction in identification of negative facial expressions (anger and fear) which can be hypothesized to improve trust and increase cooperation in these individuals. Both studies noted oxytocin was well tolerated and showed short term benefits on behavioral symptoms in individuals with FTD.

Conclusions:

Oxytocin appears to improve social aspects of cognition and behavioral symptoms in individuals with FTD and is well tolerated. However, positive data from larger and longer duration RCTs are needed before the routine use of oxytocin in individuals with FTD can be recommended.

Introduction

Over a century ago, a series of cases were described by neurologist Arnold Pick that characterized focal atrophies of the frontal cortex [Weder et al. 2007]. These cases were characterized by personality changes associated with frontal atrophy of the brain and pathological silver staining inclusions in the neurons called Pick’s bodies. This constellation of signs and symptoms was termed ‘Pick’s disease’ [Kertesz and Munoz, 2002]. Later on, research groups in Manchester, United Kingdom and Lund, Sweden termed cases that presented with frontal atrophy of the brain and associated personality and cognitive changes, but without the Pick bodies, as having ‘frontotemporal dementia’ [Graff-Radford and Woodruff, 2007].

A study from Minnesota, USA indicates that the incidence rates per 100,000 person-years for frontotemporal dementias (FTDs) were 2.2 for ages 40–49 years, 3.3 for ages 50–59 years and 8.9 for ages 60–69 years [Knopman et al. 2004]. The investigators found that the corresponding rates for Alzheimer’s disease were 0, 3.3, and 88.9 respectively. It is also estimated that the point prevalence of FTD varies between 15–22 per 100,000 [Onyike and Diehl-Schmid, 2013]. A recent study from Sweden found that the prevalence of FTD varies between 0.2–0.5% at age 70–79 years, between 2.5–3.6% at age 80–89 years and between 1.7–2.2% at age 90–95 years [Gislason et al. 2015].

FTD can be divided into three main subgroups; frontal-variant or behavioral-variant (FvFTD or BvFTD), progressive nonfluent aphasia (PNFA), and semantic dementias (SDs) [Weder et al. 2007]. These three subgroups are not precise histological subtypes of the disorder but rather reflect the distribution of pathological changes in the brain. FvFTD presents with significant personality changes, especially disinhibition, impulsivity, stereotypies, apathy and hyperorality [Weder et al. 2007]. The majority of the behavioral changes are thought to be due to orbitobasal cortical involvement, whereas apathy is associated with pathology of the medial frontal-anterior cingulate gyrus [Hodges, 2001]. In the PNFA variant of FTD, the main symptom is expressive language impairment with severe difficulty in word retrieval, whereas comprehension is intact [Weder et al. 2007]. Behavioral disturbances are not commonly seen in these individuals until later on in the illness [Boxer and Miller, 2005]. Asymmetric atrophy of the left cerebral hemisphere is seen in individuals with PNFA [Neary et al. 2005]. SDs, also called a ‘temporal variant’ of FTD, often present with a loss of word meaning and of memory for words [Boxer and Miller, 2005]. Individuals with SDs often speak fluently using substitute phrases like ‘thing’ and ‘that’. They also exhibit nonverbal deficits in both visual and auditory processing [Weder et al. 2007]. These individuals could exhibit behavioral symptoms at any time during the course of their illness but have less apathy and greater compulsivity than individuals with FvFTD [Boxer and Miller, 2005].

In a recent systematic review, Nardell and Tampi summarized the current data on the pharmacological treatments for FTDs from randomized controlled trials (RCTs) [Nardell and Tampi, 2014]. The investigators found a total of nine double-blinded RCTs for the pharmacological treatment of FTDs. Among the nine trials, two used the selective serotonin reuptake inhibitor (SSRI) paroxetine, one used trazodone, two used stimulants (methylphenidate and dextroamphetamine), one used the acetylcholinesterase inhibitor galantamine, two used the NMDA antagonist memantine, and one used the neuropeptide oxytocin. The analysis of the available data indicates that SSRIs, trazodone, amphetamines and oxytocin may be effective in reducing some behavioral symptoms in individuals with FTD and were well tolerated. However, none of these medications improved cognition in individuals with FTD.

There has been a recent interest in the use of oxytocin for psychiatric disorders. Bakermans-Kranenburg and van IJzendoorn conducted a meta-analysis that evaluated data from 19 studies where oxytocin was trialed for autism, social anxiety, postnatal depression, obsessive-compulsive problems, schizophrenia, borderline personality disorder and post-traumatic stress disorder [Bakermans-Kranenburg and van IJzendoorn, 2013]. The investigators found that oxytocin prescribed in doses ranging from 15 IU to >7000 IU showed a modest combined effect size of Cohen d = 0.32 (p < 0.01) and studies on autism spectrum disorder showed a significant combined effect size of 0.57 (p < 0.01). In a second meta-analysis that included data from 16 studies, Hofmann and colleagues found that using Hedges’ g (a variation of Cohen’s d that accounts for sample size bias) accounted for an overall placebo-controlled effect size which was moderately strong (Hedges’ g = 0.67) [Hofmann et al. 2015]. Although both these meta-analyses evaluated many studies involving patients with autism, schizophrenia, mood and affective disorders, neither of them evaluated the effects of oxytocin in individuals with FTD. Additional support for using oxytocin in individuals with FTD comes from its beneficial effects in individuals with autism, many of whom have impairments with social aspects of cognition and behavioral symptoms [Bakermans-Kranenburg and van IJzendoorn, 2013]. Furthermore, a meta-analysis of 11 placebo-controlled imaging studies found that acute oxytocin administration showed consistent alterations in activation of temporal lobes and insula especially left insula during the processing of social stimuli [Wigton et al. 2015].

Given the interest in using oxytocin for psychiatric disorders, along with the preliminary evidence that oxytocin may be beneficial in individuals with FTD [Nardell and Tampi, 2014], we sought to conduct a systematic review of the literature to identify RCTs that evaluated the use of oxytocin in individuals with FTD.

Search strategy

This systematic review was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [Shamseer et al. 2015]. The purpose of this review is to evaluate the data on the efficacy and tolerability of oxytocin in the treatment of individuals with FTD from RCTs.

We performed a literature search of PubMed, MEDLINE, EMBASE, PsycINFO and Cochrane collaboration databases through 31 August 2015 using the following keywords: ‘oxytocin’, ‘frontotemporal dementia’ and ‘randomized controlled trials.’ The search was not restricted by the age of the patients nor the language of publication of the study. However, in the final analysis we only included studies involving human patients that were published in English language journals or had official English translations. In addition, we reviewed the bibliographic databases of published articles for additional studies.

All authors reviewed the abstracts from the citations obtained via the search of the databases. The decision on which studies to be included or excluded from the final analysis was done after a review of the full text articles by all the authors. Disagreements between the authors were resolved by a consensus. The quality of included studies was assessed using the criteria developed by the Center for Evidence Based Medicine [CEBM, 2014].

Results

A total of 214 studies were identified in the literature search (Figure 1). After the removal of duplicates, a total of 152 studies remained for screening by the authors. Of these, 115 studies were excluded because they used nonhuman participants or were not RCTs. A total of 37 studies were obtained for full-text review. Of these, 35 studies were excluded because they did not include individuals with FTD (31), did not test oxytocin (1), or did not have a randomized controlled study design (3).

Figure 1.

PRISMA flow diagram.

This systematic review of the literature only identified two RCTs that evaluated the use of oxytocin in individuals with FTD [Jesso et al. 2011; Finger et al. 2015]. Both studies were of good quality based on the criteria developed by the Center for Evidence Based Medicine [CEBM, 2014]. The only limitation noted was that in the Jesso and colleagues study it was unclear if individuals in the oxytocin and placebo groups were similar prior to randomization [Jesso et al. 2011] (Table 1).

Table 1.

Quality of studies reviewed.

Name of study	Randomization?	Similar groups initially?	Equal treatments?	All participants accounted for?	Analyzed in groups to which they were randomized?	Objective/‘blind’ treatments?
[Jesso et al. 2011]	Yes	Unclear	Yes	Yes	Yes	Yes
[Finger et al. 2015]	Yes	Yes	Yes	Yes	Yes	Yes

The study by Jesso and colleagues utilized a cross-over design with a single dose of oxytocin at each phase of the cross-over, with same day measurements of both outcome and safety measures [Jesso et al. 2011]. Telephone assessments for any washout effects were conducted 7 days after each dose. Cross-over occurred after 14 days of washout. Dosing of oxytocin was 24 IU. The study by Finger and colleagues had a parallel, dose-escalation design, with doses of 24 IU twice daily, 48 IU twice daily or 72 IU twice daily respectively for 7 days [Finger et al. 2015]. Outcome and safety measures were conducted on day 7. Telephone assessments for any unanticipated effects of medication discontinuation were conducted 7 days after medication washout. Both studies utilized placebo as a comparator. There were 20 and 23 participants in the two studies, respectively (Table 2).

Table 2.

Summary of included studies.

Name of study	Total number of participants	Age of participants, years		Type of setting	Comparators	Duration of trial
		Mean	Range
[Jesso et al. 2011]	20	64.4	57–72	Clinical research unit	Intranasal oxytocin (24 IU) versus placebo	One-time dose with same-day assessment. Follow up on same day of dosing and 7 days after dosing to assess for adverse effects. Cross-over at day 14 with similar protocol.
[Finger et al. 2015]	23	64.5	53–80	Clinical research unit	Intranasal oxytocin (24, 48, and 72 IU) versus placebo	Twice-daily dosing for 7 days with assessment on day 7. Follow up on day 14 to assess for adverse effects. No cross-over.

Quantitative measures to assess response to oxytocin included emotional recognition and behavioral rating scales. Neither study reported any significant adverse events associated with oxytocin use (Table 3).

Table 3.

Summary of results from included studies.

Name of study	Rating scales	Outcomes	Tolerability
[Jesso et al. 2011]	Emotional recognition:		No significant adverse events reported.
	Facial Expression Recognition and Intensity Task	Significantly reduced recognition of angry expressions with oxytocin. No significant main effects of treatment nor emotion.
	Vocal Affect Recognition Task	No significant main effects of treatment on emotion.
	Mind in the Eyes Task	Significantly worse performance with oxytocin.
	Behavioral scales
	Neuropsychiatric Inventory	Significant improvement in score overall on day 1 with oxytocin, but not on any individual sub-items.
	Frontal Behavioral Inventory	Nonsignificant trend towards improved behavior scores on day 1 with oxytocin
[Finger et al. 2015]	Neuropsychiatric Inventory Interpersonal Reactivity Index Frontal Behavioral Inventory Multifaceted Empathy Task Clinician’s Global Impression Clinical Dementia Rating for Frontotemporal Dementia Frontotemporal Dementia Rating Scale Apathy Evaluation Scale	Significance not reported due to small sample size. Trends in improvement on NPI apathy, FBI apathy, and IRI empathic concern scales with oxytocin. No significant differences between groups on nonsocial aspects of cognition.	No significant differences in vital signs or serum sodium levels between treatment groups.

FBI, Frontal Behavioral Inventory; IRI, Interpersonal Reactivity Index; NPI, Neuropsychiatric Inventory.

The study by Jesso and colleagues found a mixed change in recognition of expressions in the oxytocin group; there was reduced recognition of angry expressions but increased recognition of happy and intense expressions [Jesso et al. 2011]. The only significant treatment and emotion interaction was a reduction in recognition of angry faces following oxytocin administration. There was no significant difference in recognition of vocal affect between the oxytocin and placebo groups. Emotional recognition through eyes (Mind in the Eyes Test) was significantly worse in the oxytocin group. The Neuropsychiatric Inventory (NPI) and Frontal Behavioral Inventory (FBI) showed significant improvements after a one-time dose of oxytocin.

The study by Finger and colleagues did not report significance for measures given the small sample size [Finger et al. 2015]. Trends were found in improvements on the NPI, FBI, and the Interpersonal Reactivity Index (IRI) in the oxytocin group. Other measures (Front Temporal Lobar Degeneration-Modified Clinical Dementia Rating, Multifaceted Empathy Task, and Clinician’s Global Impression) did not show any difference between the oxytocin and placebo groups, although the researchers stated that a small sample size precluded further statistical analysis. Nonsocial aspects of cognition were not significant between groups. Vital signs and serum sodium levels were similar between groups.

Discussion

This is the first systematic review of literature that evaluated the use of oxytocin in individuals with FTD from RCTs. The data from this review indicate that although there is growing evidence for the use of oxytocin from controlled studies for various psychiatric disorders, especially schizophrenia and autism spectrum disorders, there is a clear dearth of similar studies in individuals with FTD. We only found two RCTs for the use of oxytocin in individuals with FTD.

Available data from the two RCTs indicate that oxytocin is well tolerated in individuals with FTD. In the study by Jesso and colleagues, the use of oxytocin in individuals with FTD produced a reduction in identification of negative facial expressions (anger and fear), which can be hypothesized to improve trust and increase cooperation in these individuals [Jesso et al. 2011]. It is not surprising that effects were not maintained on day 7, given the short half-life of a single dose of oxytocin. Both studies noted short-term benefits on the NPI and the FBI in individuals with FTD who received oxytocin. Based on the available data, we can conclude that oxytocin may improve social aspects of cognition and behaviors in individuals with FTD, but the data must be considered preliminary and the routine use of oxytocin in these individuals cannot be recommended at this time.

The strengths of this review include a comprehensive search of five large databases, adherence to the PRISMA guidelines for systematic reviews, and the use of CEBM criteria for assessing the quality of included studies. One major limitation of this review is the lack of RCTs that assess the use oxytocin in individuals with FTD. Additionally, both studies had a limited number of participants, were of short duration, and used different study designs.

Conclusion

This systematic review indicates that evidence from controlled studies for the use of oxytocin in individuals with FTD is scarce. Available data from two studies indicate that oxytocin is well tolerated in individuals with FTD. Additionally, oxytocin appears to improve social aspects of cognition and behavioral symptoms in individuals with FTD. However, positive data from larger and longer duration RCTs are needed before the routine use of oxytocin in individuals with FTD can be recommended.