Symptoms of anxiety and depression in patients with amyotrophic lateral sclerosis and their relatives during the disease trajectory

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Introduction
Amyotrophic lateral sclerosis (ALS) is a devastating disease that gradually results in muscle atrophy and weakness, with median survival between two to five years from onset of symptoms (1).During the disease trajectory, the patients and relatives must adjust continuously to new losses in the patient's physical functions and new situations that arise in their daily living (2).
Despite the progressive nature of ALS and the knowledge that psychological well-being affects quality of life (3,4), coping (5) as well as survival time in patients with ALS (6,7), there are few studies that examine the occurrence of symptoms of anxiety and depression from the time of diagnosis and over time.Results from previous studies show a variation in the prevalence of anxiety and depression in patients with ALS.Most studies indicate that clinically significant depression and anxiety are not as present or as severe as might be expected in ALS patients (8)(9)(10)(11)(12)(13)(14)(15), while other studies show that emotional distress is common (10,(16)(17)(18)(19).Studies have also found that despite the progressive decline in muscle function, the psychological well-being seems to be stable during the disease progression (13,20) and not related to the patient's physical function (11,20).
The disease also affects the family because of the different symptoms that occur during the disease progression (21).Family members are often involved in the care for their sick relative, and caring for a family member with ALS involves physical, emotional and social challenges, including managing different practicalities, limitations and restrictions, and impact on relationships due to the ALS disease (22,23).Previous studies have found that relatives' psychological distress is related to their perceived strain (24)(25)(26)(27).The burden among ALS caregivers is severe (26), and both anxiety and depression are significant predictors of caregivers' burden (22,26,28).Moreover, lack of social support contributes to psychological distress (29).The results regarding psychological distress (i.e.anxiety and depression) among relatives of patients with ALS, are similar to studies involving patients, often variable.The results show that psychological distress is relatively uncommon in caregivers (30)(31)(32), while others found it to be relatively common (17,33).
Although several studies have been conducted to evaluate psychological well-being among patients with ALS and their relatives, most studies have focused on depression and only a few on anxiety (34).
To our knowledge, there are few studies that have explored the prevalence of both anxiety and depression among patients newly diagnosed with ALS and their relatives during the disease progression.The aim of the present study was, therefore, to describe the presence of anxiety and depression among patients with ALS and their relatives from the time of diagnosis and during the disease progression.Another aim was to explore if the patient's physical function correlated with the patients' or relatives' anxiety and depression.

Design
This was a prospective and longitudinal study where patients and their relatives filled out the Hospital Anxiety and Depression Scale (HADS) at five measurement time points (1-3, 6, 12, 18 and 24 months after diagnosis).

Participants
A total of 33 patients, who met the criteria for a diagnosis of definite or probable ALS according to the El Escorial criteria (35), accepted to participate in the project and were asked to identify a close relative who could take part in the study.All relatives that were asked accepted participation.The patients and relatives were recruited from three hospitals with a multidisciplinary ALS/MND team in Sweden.The participants had to be 20 years or older and be able to understand and express themselves in the Swedish language.Patients with a serious disease other than ALS or dementia were excluded.

Data collection
The Hospital Anxiety and Depression Scale (HADS) is a self-reported scale, comprising two subscales measuring the presence and severity of anxiety and depression over the past week (each subscale consists of 7 items).All questions are rated on a 4-level scale (0-3 points) with a range from 0 (no distress) to 21 (maximum distress).In the present study, the cut-off score for the two subscales is 8-10 = doubtful cases and ≥ 11 = valid cases (36).The questionnaire was filled out separately by the patients and their relative.
The patient's physical function was measured with the revised Amyotrophic Lateral Sclerosis Functional and Rating Scale (ALS FRS-R).The scale consists of 12 questions where the patient's physical function (fine-and gross motor task, respiratory function and bulbar function) is graded from 0 = total loss to 4 = normal function (37).The first author (a nurse with extensive experience and knowledge of ALS) performed the data collection, including filling out the ALS FRS-R at all five measurements.

Data analysis
Descriptive statistics were used to describe the demographic and clinical characteristics of the participants in the study.Correlations between HADS and ALS FRS-R were analysed using Spearman's rho.
Differences in anxiety and depression from diagnosis and over time in the group of patients and relatives were analysed using a mixed model, with corresponding 95% confidence interval.Subject was included as random effect in the models.Significance level was p = 0.05 (twotailed).P-value was not adjusted for the number of tests.For statistical analysis, the SPSS version 27 (SPSS Inc.Chicago, IL, USA) and R version 3.1.1were used.

Results
Data collection was conducted at five time points (TP1 = 1-3 months, TP2 = 6 months, TP3 = 12 months, TP4 = 18 months and TP5 = 24 months after diagnosis).A total of 33 patients and their relatives were included in the present study.Of these, 2 patients and their relatives were overlooked at time point 1 but were included at time point 2. The drop-outs were due to patients being too ill (n = 2) or because they passed away (n = 20), further data were not collected from the relatives.The characteristics of the participants are described in Table 1.

Presence of anxiety and depression among patients and their relatives and change over time
The results showed that many patients (45%) and relatives (58%) scored above the cut-off for doubtful cases/clinical cases on HADSa at TP1, indicating that the symptom of anxiety is relatively common soon after the patient has been diagnosed with ALS.Thirteen per cent of the patients and 29% of the relatives scored above the cut-off for doubtful cases/clinical cases on HADSd at TP1 (Table 2).
There was a significant change in the mean score for the HADSa over time within the group of patients, but not on the HADSd.No changes were seen within the group of relatives over time on HADSa or HADSd (Table 3).When comparing the score on the HADSa and HADSd, the results showed that relatives had significantly more symptoms of anxiety compared to patients at base-line and over time, and that it was the same participants who had symptoms of anxiety and/or depression during the disease progression.No difference was shown between patients and relatives on the HADSd (Table 4).
Even though several patients and relatives had symptoms of anxiety and/or depression at the follow-up assessments (TP2, 3, 4 and 5), few relatives received antidepressant and/or anxiolytic treatment (Table 2).In total, there were 15 patients and 11 relatives that scored with in the cut-off for doubtful cases or clinical cases at some time points who had no treatment for their symptoms.One patient and three relatives were identified as having symptoms of anxiety and/or depression despite them receiving antidepressant/anxiolytic treatment (data not shown).

Correlations between physical function, anxiety and depression
There was a positive correlation between HADSa and HADSd in the patient group at TP 2. This positive correlation between the two subscales of HADS was seen at all five time points in the group of relatives.At TP 4, there was a positive correlation between patients and relatives on the HADSa (Fig. 1).Even though the patients' physical disabilities (measured with ALS FRS-R) increased during the disease trajectory (Table 2), no correlations were shown between the patients' physical function (ALS FRS-R) and their psychological well-being (HADS) at the different time points.However, there was a negative correlation between the patients' physical function and the relatives' psychological well-being (HADS) at the three last assessments (Fig. 1).

Psychological well-being among patients and their relatives and change over time
To our knowledge, this is one of a few prospective and longitudinal studies with a focus on both anxiety and depression in patients newly diagnosed with ALS and their relatives.The results show that almost half of the patients (48%) had symptoms of anxiety soon after they had been diagnosed with ALS, but the number decreased over time.A few patients were considered as clinical cases on the two subscales of HAD, but there were many patients who had symptoms of anxiety soon after they had been diagnosed with ALS.The prevalence (i.e.mean score and number of persons) of anxiety decreased during the first six months after diagnosis, and there were only a few patients with symptoms of anxiety during the later stages of the disease.This high prevalence of anxiety quite early after a diagnosis and decreasing prevalence during the first year were also seen in the study by Vignola et al. (18).When comparing the results from different studies, it is important to consider how the concept of interest, e.g.anxiety and depression, has been measured.The discrepancy in the prevalence reported in the studies can be explained by measurements capturing different aspects of anxiety and depression.In their study, Vignola et al., used a different way to measure anxiety and depression, but despite that, we came to the same result.Hence, even if you measure anxiety and depression with different instruments, the prevalence is the same.However, it is worth noting that our study had the same participants throughout the study.However, in the study by Vignola et al., there was one group with patients in the diagnostic phase and another group in the follow-up phase (18).
This high level of symptoms of anxiety early on after being diagnosed with ALS could be a natural psychological reaction due to the life threating diagnosis.It could also be that during the disease trajectory, the patient adapts to the disease and the changes that result, which may explain the decrease in symptoms of anxiety despite the increased physical impairment.Since there are only a few studies on anxiety, including newly diagnosed patients, it is difficult to draw any conclusion, but it should be taken into account as a possible explanation.
Symptoms of depression were relatively uncommon in our study, where the highest prevalence was measured six months after diagnosis (20%), which then decreased to below 10% at the other assessments.This low prevalence of depression was also seen in the study by Ferentinos et al., where almost 65% of the patients were included within three months following their diagnosis, indicating that depression is relatively uncommon in newly diagnosed patients (12).Even in those studies with a wide variation in the time for diagnoses, the prevalence of depression is often uncommon (3,11,17), and not as present at or as severe as could be expected due to the characteristics of ALS.This low prevalence of depression among patients with ALS, despite the devastating nature of the disease, is often described as being due to many

Table 4
Differences between the patients and relatives on the two subscales for HADS.patients receiving treatment with anti-depressants for their problems with sialorrhea and/or pseudobulbar effect.However, this cannot explain the low prevalence in our cohort, where only a few patients were treated with anti-depressants.Our study supports the results of previous studies, showing that the prevalence of symptoms of anxiety and depression remains stable despite a decline in the physical function (13,20,38).This low prevalence of anxiety and depression over time in our cohort could be an indication of successful psychological adjustment to the disease and the patients received good support from the healthcare professionals.Nonetheless, further longitudinal studies are needed on this subject to be able to draw any conclusion.Also, in the group of relatives, the results showed a high prevalence of symptoms of anxiety during the first year after diagnosis, but in contrast to the group of patients, the symptoms remained stable at a high level during the disease progression.This high level quite early after diagnosis is consistent with the study by Vignola et al. (18).During the first year, 50% of the relatives had symptoms of anxiety (i.e.doubtful or clinical cases), and it was only at the last assessment that the prevalence decreased under 40%.In the study by de Wit et al., >40% of the relatives were considered as being psychologically distressed (i.e. the sum of HADS total score, HADS-T) shortly after their relative was diagnosed with ALS, and the level of distress increased over time (39).This is in contrast to our results where the level of anxiety and/or depression remained stable.
In most studies, the prevalence of symptoms of psychological distress (i.e.anxiety and depression) among relatives is lower compared with the results from our study.This lower prevalence is regardless of the use of measurement instruments.In a study by Conroy et al. (2021), including three specialist ALS clinics in three different European countries, there was a significant difference in the symptoms of anxiety in groups of caregivers (mostly family) (40).It is important to take into account countries with different cultures, populations, healthcare systems and economies when comparing results from different countries.
Most often, the relatives focus on the patient and not on their own needs, and the focus is on practical help rather than emotional support (41).The high prevalence of symptoms of anxiety during the disease progression in our study highlights the need for health-care professionals to more actively pay attention to symptoms of anxiety and/or depression among the relatives.Since relatives are often involved in the patient's care, and the patient is dependent on the relative's ability to manage their situation, it is important to offer support and treatment to relatives as well.
It is also worth noting that one patient and three relatives with treatment for anxiety and/or depression still had symptoms, which highlights the importance of actively screening for symptoms of anxiety and depression from the time of diagnosis and over time to detect those with insufficient treatment.

Difference between patients and relatives
The results show that the relatives more often had symptoms of anxiety and/or depression compared with the patients during the disease progression, which is in accordance with other studies (33,42).One explanation could be the burden felt by the relatives.Several studies have shown that caregiver burden is positively related to psychological distress (22,26,28,43).Moreover, relatives are often involved in the patient's care, taking great responsibility for them and dedicating many hours to help their sick relative (8,44,45).

Correlation between psychological well-being and physical function
In accordance with other studies (10,17,46,47), our results showed that the patients' physical function did not seem to have a negative impact on the patients' psychological well-being, as could be expected due to the disease characteristics, and that their psychological wellbeing remained stable despite the progressive decline in physical function.However, in the group of relatives, we found a correlation between symptoms of anxiety and/or depression and the patient's physical function, which also has been shown in some studies (48,49), but is in contrast to others (17,50).Perhaps the difference in our results compared with earlier studies could be due to the fact that we only included newly diagnosed patients and their relatives.Another explanation could be the different social insurance system in different counties, with more or less practical and economic support during the disease trajectory.It is, therefore, important to not only focus on the prevalence but also explore the cause of the psychological distress to better help and support patients and relatives during the disease progression.
The present study only explored the prevalence of symptoms of anxiety and depression from the time of diagnosis and over time.However, it did not take into account other factors that can explain the levels of psychological distress in patients with ALS and their relatives.Further research is needed, probably with both quantitative and qualitative measurements, to get a deeper knowledge and understanding of the prevalence but also of factors that contribute to symptoms of anxiety and depression.
One strength of the present study is the prospective design, following patients newly diagnosed with ALS and their relatives over time, which provides important knowledge on emotional distress during the disease progression.Another strength is that there was only a small number of dropouts.This was attributed exclusively to patients being too ill or passing away, which reflect the rapid progress of the disease.However, only one third of patients and relatives was evaluated at the last assessment which must be taken into account when interpreting the data.
One limitation of this study is the small sample size.The 33 patients and their relatives who participated in the study may, however, be considered sufficient, as this is a vulnerable and seriously ill group of patients.Another limitation was the lack of information on previous symptoms of anxiety and depression among the participants and relatives.This means that we cannot say if it is the disease that contributes to symptoms of anxiety and/or depression or if the disease reinforces these symptoms.We have not performed any formal cognitive test; however, the cognitive function was judged by their physician before inclusion.The first author (BJL), performed all data collection and did not notice any signs of cognitive impairment in the patients when the data was collected.However, this cannot guarantee that this did not occur, which may be taken into consideration when interpreting the results.It is also a limitation that we only used one instrument to measure anxiety and depression.Most standard questionnaires contain items assessing somatic symptoms, which may be confused with the symptoms of ALS.However, the HADS questionnaire was considered valid, as it does not focus on somatic symptoms that can be confused with the symptoms of ALS (37).

Conclusion
The results showed that many patients and relatives suffered from symptoms of anxiety quite soon after the diagnosis, and that many relatives had symptoms of anxiety during the disease trajectory.This highlights the need to continuously measure symptoms of anxiety/ depression in patients but also to pay attention to symptoms among relatives.A better understanding of and knowledge on the prevalence of anxiety and depression from the time of diagnosis and over time, in both patients and relatives will probably contribute to better and more efficient care during the disease trajectory.

Fig. 1 .
Fig. 1.Correlations between the two subscales of HADS and the patient's physical function during the disease progression.The colour scale of the shape ranges from dark red (strong negative correlation), white (no correlation) to dark blue (strong positive correlation).The shape of the ellipse illustrates the strength of the correlation where a narrower ellipse indicates a stronger relationship.SUMALSFRS = patient's physical function, SUMANX/SUMDEP = patients, sumanx/sumdep = relatives.(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Table 1
Characteristics of the study groups.

Table 2
Mean score for the ALS FRS-R, HADS and number of participants with anxiolytic/antidepressant treatment at the different timepoints.

Table 3
Change within the groups of patients and relatives on the two subscales for HADS.