Psychotherapy and pharmacotherapy interventions to reduce distress or improve well-being in people with amyotrophic lateral sclerosis: A systematic review.

Our objective was to systematically review and critically evaluate the evidence for psychotherapy and pharmacotherapy interventions for reducing distress or improving well-being in people with amyotrophic lateral sclerosis (pwALS). Online bibliographic databases and clinical trial registers were searched and an assessment of study quality was conducted. Seven thousand two hundred and twenty-three studies were identified, of which five met inclusion criteria (four completed and one in progress). All studies examined psychotherapeutic interventions, and no studies investigated pharmacotherapy. Two studies adopted a randomized controlled trial design, one a controlled trial design and two a cohort design. Sample sizes were small in all studies (overall n = 145). The quality of completed studies was generally poor, with evidence that all were at potential risk of bias in numerous areas. Improvements in well-being were found with expressive disclosure (compared to no disclosure), cognitive behavioural therapy/counselling (compared to non-randomized pharmacotherapy) and hypnosis in the short term only, while no improvements were seen with a life review intervention. In conclusion, there is currently insufficient evidence to recommend the use of specific psychotherapy interventions for reducing distress or improving well-being in pwALS, and no evidence to support pharmacotherapy interventions. Research is urgently needed to address these significant gaps in the literature.


Introduction
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative disease for which there is no cure, prognosis is poor, and median survival is 2 -3 years following symptom onset (1). Given its devastating consequences, it is unsurprising that some pwALS may experience distress during the course of the condition (e.g. low mood, fearfulness, hopelessness, pessimism, loneliness and despair). Estimated prevalence rates of depressive and anxiety disorders vary markedly from 0 to 44% for minor or major depression and 0 to 30% for anxiety, although rates vary depending on how they are assessed (2 -4). For example, mood disorders may be under-or over-identifi ed depending on the use of self-report measures vs. structured psychiatric interviews (lower

REVIEW ARTICLE
Psychotherapy and pharmacotherapy interventions to reduce distress or improve well-being in people with amyotrophic lateral sclerosis: A systematic review comparable disease profi les, and are higher than those found in the general population (4).
One important potential outcome for pwALS is an increased risk of assisted/non-assisted suicide. A study in Sweden reported that the relative risk of suicide was almost six times greater in pwALS than in age-and gender-matched individuals in the general population (7) -a fi gure higher than reported in MS, PD and malignant cancers. Furthermore, pwALS appear to be at particular risk of suicide and suicidal ideation following diagnosis and in the year following the fi rst period of hospitalization (7,8). The contribution of mood disorders to increased suicide risk is likely to be complex as some prospective studies have shown that wishes to hasten death or requests for euthanasia/assisted suicide are associated with depression and/or anxiety (9), while others have not (10). Another study reported higher scores for suicidal ideation, demoralization and hopelessness in pwALS compared to metastatic cancer, despite comparable scores for depression (11). Feelings of loneliness, low quality of life, perceptions of being a burden on others and hopelessness appear to be other important determinants (9,12,13), suggesting that such feelings are valid targets for treatment even in the absence of clinical depression or anxiety disorder.
Even in those who do not choose to shorten their own lives, distress is associated with an increased risk of mortality and poorer quality of life. One study reported an almost seven times greater risk of mortality in pwALS experiencing distress compared to those experiencing well-being (14), while another reported that low mood at six weeks post diagnosis predicted poorer survival at six months (15). In addition, signifi cantly shorter median survival times have been found in those experiencing distress compared to those with high levels of well-being (333 vs. Ͼ 1200 days, respectively), together with a poorer quality of life (14,16).
Given these associations between distress and risk of suicide/mortality/poorer quality of life, it is imperative that distress is adequately treated in pwALS. However, relatively little is known about how this might be achieved. Current recommendations for the management of depression and anxiety in adults with chronic physical health conditions and terminal illness include treatment with pharmacotherapy (e.g. anti-depressants or anxiolytics), psychotherapy (e.g. cognitive behavioural therapy (CBT)), or a combination of both depending on the severity of the disorder (17 -20). Guidelines issued by the European Federation of Neurological Societies (EFNS) Task Force on Diagnosis and Management of ALS (21) state that depression should be treated with an appropriate anti-depressant (e.g. amitriptyline, mirtazapine or a selective serotonin reuptake inhibitor), while anxiety should be treated with bupropion or benzodiazepines, although no evidence has been cited to support these recommendations. Furthermore, no recommendations were made in relation to psychotherapy. Others have suggested that modifi cations or adjuncts to conventional CBT may be of value in addressing the particular psychological needs of pwALS (3), although evidence to support these proposals is lacking. Certainly, a lack of research on the effi cacy of psychological interventions for pWALS has previously been noted (22). Consequently, the aims of this review were to systematically review and critically evaluate the evidence for psychotherapy and pharmacotherapy interventions for reducing distress or improving well-being in pwALS.
All fi elds were searched including medical subject headings. In addition, the terms ' amyotrophic lateral sclerosis ' OR ' motor neuron disease ' OR ' motor neurone disease ' OR ' Lou Gehrig's disease ' were used to search the following databases and registers: Cochrane Central Register of Controlled Trials; WHO International Clinical Trials Registry Platform (a search portal containing data from 15 international clinical trial registers); and Open Grey (an online grey literature database). References of published reviews and studies were also manually searched.

Inclusion/exclusion criteria and study selection
Studies were included if they met the following criteria: Evaluated any type of study design (e.g. rand-• omized controlled trial design (RCT), controlled trial (CT), cohort study or case-control), with the exception of case reports; Included participants with a diagnosis of • ALS; Involved a form of psychotherapy or pharma-• cotherapy aimed at reducing distress or improving well-being (where distress or well-being was included as a primary outcome measure). Psychotherapy was defi ned as any face-to-face or self-help intervention employing common psychotherapeutic techniques such as cognitive restructuring, psycho-education, guided visual imagery, life review, or facilitation of emotional expression; Published in any language as a journal article, • conference abstract, dissertation or thesis.
Titles and study abstracts were initially screened in order to determine eligibility for retrieval. Retrieved articles were then screened for eligibility and selected for inclusion using a structured proforma. Studies were independently screened and selected by two authors (RLG and MCC), and disagreements were resolved through discussion.

Assessment of study quality and data extraction
Study quality was assessed using the Cochrane Collaboration ' s Risk of Bias Tool (23), which assesses study quality in fi ve areas of bias known to affect clinical outcomes: sequence generation, allocation concealment, blinding of participants/outcome assessors, incomplete outcome data, and selective outcome reporting. The quality of studies was independently rated by two authors (RLG and MCC), with disagreements being resolved through discussion. Potential sources of patient heterogeneity and factors that may confound or infl uence the interpretation or generalizability of results were also identifi ed in each study. In addition, data on a range of clinical and research variables were independently extracted from each study by two authors (RLG and MCC), and discrepancies were resolved through discussion.

Study characteristics
Seven thousand two hundred and twenty-three studies were identifi ed. Of these, fi ve were selected after screening (24 -30). Four studies have been completed to date (24,26 -29) and one is in progress (30) (see Figure 1, Table I). All studies examined psychotherapeutic interventions, and no studies investigated pharmacotherapy. Two additional studies failed to recruit pwALS: one open-label phase III trial attempted to explore the use of escitalopram for major depression in pwALS/MS (31), and one cohort study of Coping Effectiveness Training in pwALS and/or their caregivers was withdrawn prior to enrolment (32). Another RCT is reportedly under way of a meditation training programme modifi ed for pwALS/carers (33), although details are unknown as it has not been registered on any clinical trial database.
Of the fi ve studies identifi ed, two adopted a RCT design (both with a maximum follow-up interval of six months) (24,30), one adopted a CT design (28) and two adopted a cohort design (Pre-vs. Post-) (26,27,29). The majority of studies recruited participants from outpatient clinics, with one study recruiting from both the community and outpatient clinics (24) and one study recruiting from just the community (26,27) Completed (n = 4) Ongoing (n = 1)

Studies excluded (n = 33):
Duplicates (n = 26) Intervention protocol (n = 2) Study aimed to recruit people with ALS but was unable to achieve this (n = 2) Only reported caregiver-related outcomes (n = 1) Repetition of data in a different format to an included study (n = 2) Dissertation (n = 1) Conference abstract (n = 1) Figure 1. Flow of studies in the systematic review. where they were selected for the presence of significant depression/anxiety/distress, with the exception of one which required that participants score in the clinical range on a mood questionnaire in order to be randomly allocated to a psychotherapy condition (30). The type of psychotherapeutic intervention differed in all studies (two articles reported data from the same participant sample (26,27)), and all but one involved face-to-face therapist contact. A nonactive control condition was used in three studies (24,28,30), while two lacked a control condition (26,27,29) and no studies employed an active control condition. The number of participants ranged from eight to 54 in the completed studies (24,26 -29), while the anticipated number for the ongoing study was 40 per condition (30). In the completed studies, participants were typically middle-aged to older males who had received a diagnosis of ALS within the previous three years.

Study fi ndings
The only psychotherapy RCT completed to date involved self-help expressive disclosure (i.e. facilitation of emotional expression) in which participants were required to write or talk about their deepest thoughts and feelings in relation to their experience of ALS during a one-week period (24). Participants in the disclosure condition reported signifi cantly higher levels of well-being than those in the no-disclosure condition at three but not six months post intervention, although this effect was moderated by ambivalence over emotional expression. The authors did not examine well-being immediately after the intervention and so the immediate short-and longerterm effects (beyond six months) are unknown. A non-randomized CT comparing CBT combined with counselling techniques with pharmacotherapy reported signifi cant pre-post differences in depression and anxiety in the intervention but not control group (28). However, signifi cant between-group differences in anxiety and time since diagnosis were found at baseline and not subsequently controlled for. In addition, the longer-term effects of the intervention are unknown as there was no follow-up. Two pre-post cohort studies have been completed to date: one evaluated dignity therapy (26,27) and one evaluated a hypnosis-based intervention (29). Dignity therapy comprised a brief life-review intervention in which pwALS were encouraged to refl ect on signifi cant memories, events and accomplishments in their life. No signifi cant pre-post differences in levels of hopefulness, dignity or spiritual well-being were observed; an unsurprising result given that high levels of hopefulness, low levels of dignity-related distress and moderate levels of spiritual well-being were reported at baseline. The hypnosis based intervention involved hypnotic suggestion with guided visual imagery, together with training in selfhypnosis. Signifi cant pre-post decreases in depression, anxiety, and some aspects of quality of life were reported. Again, the longer-term effects of dignity and hypnosis based therapy are unknown as there was no follow-up in these studies.
Results are currently awaited for one further study: a multicentre RCT of exercise therapy vs. CBT vs. usual care (30). In this study CBT will address ALS-specifi c issues (e.g. coming to terms with the diagnosis, coping with mood issues, and maintaining autonomy, activities and relationships), and will be delivered in a modular format, with the choice of modules being individually tailored to pwALS and their caregivers. Similar to previous studies, although this study will be able to inform about the shorter-term effects of psychotherapy (up to six months), the longer-term effects remain unexplored. Further details about the results of these studies are highlighted in Supplementary Table I

Quality assessment and critical appraisal
As shown in Table II, the quality of completed studies was variable but generally poor, with risk of bias only being adequately addressed in 1 -2 areas. Incomplete outcome data was the area most adequately addressed, while blinding of participants was the least adequately addressed. No study included an adequate placebo that ensured participants could be blinded to the research question, and only one study reported blinding of outcome assessors (30). A truly random sequence generation was used in only one study (24), and allocation concealment was unclear in the majority of studies. There was evidence of selective outcome reporting in one study (24).
A number of potential sources of patient heterogeneity and factors that may confound or infl uence the interpretation or generalizability of results were also identifi ed (see Table III). With regard to patient heterogeneity, one study did not report using revised El Escorial criteria for diagnosing ALS (26,27) and two studies did not report site of ALS onset (limb/ spinal vs. bulbar) (24,26,27), and so the variability in presentations across studies, and subsequent impact on results, is unknown. Distress or well-being was not specifi ed as an inclusion criterion in four studies (24,26,27,29) (but was implied in one study where anti-depressant use was an inclusion criterion (24)), and so it is unclear how many participants were experiencing signifi cant depression/anxiety/ distress. This may have impacted on results as intervention trials that include non-distressed patients are less likely to show benefi cial effects.
Turning to other factors that may confound or infl uence the interpretation of results, four studies completed screening of cognitive abilities (24,26,27,29,30), although details were frequently lacking. However, the exclusion criterion for cognitive impairment in two studies meant that some participants may have been experiencing mild-to-moderate cognitive impairment (as noted in one study) (24,26,27). Concurrent psychotherapy or pharmacotherapy were permitted in three studies (24,26,27), and so the extent to which this may have impacted on results is uncertain, especially since these variables were not controlled for in statistical analyses. With regard to treatment fi delity, no study reported using a therapy manual and only one employed therapist adherence checks (26,27). Furthermore, no study employed an active control condition. Consequently, the extent to which benefi cial effects were attributable to the prescribed psychotherapy, additional therapeutic components introduced due to lack of treatment fi delity, or non-specifi c therapeutic factors (e.g. therapist attention and social support) is unclear. In addition, the extent to which benefi cial effects may have been attributable to potential anti-depressant effects of riluzole (34,35) was also uncertain given that no studies reported on its use. Finally, generalizability of results was limited in two studies in which self-referrals were permitted (24,26,27), since those self-referring may not be representative of the ALS population.

Discussion
The aims of this review were to systematically and critically evaluate the effectiveness of psychotherapy and pharmacotherapy interventions for reducing distress or improving well-being in pwALS. Five studies of psychotherapy and no studies of pharmacotherapy were identifi ed. Improvements in wellbeing were reported in three out of four completed studies in the short term only, but were not investigated beyond six months follow-up. The quality of the completed studies was relatively poor, as all were at risk of bias in a number of areas. However, it should be stressed that this is an issue common to other reviews of psychotherapy interventions rather than being specifi c to studies in pwALS (36,37). Furthermore, sample sizes were small (overall n ϭ 145), which may be a refl ection of the challenges that come with recruiting participants with ALS into research studies (e.g. the prevalence of ALS, the typical survival rate and tolerability to engaging in such studies). In addition, there was considerable heterogeneity in the interventions, outcome measures and study designs used, as well as the clinical presentation of participants. Consequently, at present, there is insuffi cient evidence to support the use of specifi c psychotherapy interventions for reducing distress or improving well-being in pwALS. This is despite a previous call for research on the effi cacy of psychological interventions in this population (22). Moreover, there is a lack of evidence for pharmacotherapy interventions at this time. Neither of these fi ndings should be interpreted as proof of ineffectiveness, but instead highlight the signifi cant gaps that exist in the current literature. Both studies report data from the same participant sample (see Table I for further explanation). CT: controlled trial; RCT: randomized controlled trial. Both studies report data from the same participant sample (see Table I

Clinical recommendations
Although previous authors (3,21,22,38) have suggested the use of a variety of pharmacotherapies and/ or psychotherapies for reducing distress or improving well-being in pwALS, no specifi c evidence based clinical recommendations can be made at this time.
Suggestions from clinical practice have generally been based on what is known to be effective in working-age and older adult populations with mood disorders, but can also be drawn from existing literature on psychotherapy interventions for those with progressive degenerative neuromuscular disorders. For example, while the evidence base is relatively small, a recent review notes the potential importance of Acceptance and Commitment Therapy in such populations, given the potential role of acceptance as a mediating factor in the relationship between disease symptomatology and quality of life (39).

Research recommendations
There is a pressing need to examine pharmacotherapy and psychotherapy interventions within high quality, multi-site, double-blind RCTs, both in the short and longer term, before any strong conclusions can be drawn about their effectiveness in pwALS. Clarifying these points further, multi-site RCTs of pharmacotherapy and psychotherapy interventions may be one way of improving sample sizes given the challenges noted above of recruiting pwALS into intervention studies. Although blinding of participants in psychotherapy RCTs is diffi cult, it is not impossible, as illustrated in previous studies that have employed adequate ' talking controls ' for psychotherapy interventions (40,41). Finally, it is important to assess outcomes in the longer term, as well as the shorter term, as any gains in well-being may be short lived, given the rapidly progressive nature of ALS. With respect to specifi c recommendations for pharmacotherapy interventions, as previous reviews have suggested the use of citalopram, venlafaxine, amitriptyline, nortriptyline or mirtazapine for depression, and bupropion, diazepam, lorazepam or midazolam for anxiety (21,38,42), examining these would be an obvious place to start. Studies of psychotherapy interventions could evaluate the effectiveness of interventions such as CBT or mindfulness-based therapy, modifi ed to meet the needs of pwALS, as suggested previously (3,33). Such studies could also assess the benefi ts of including caregivers in the interventions given that this may not only help improve their well-being, but also that of the cared-for person (43,44). In addition, such studies could focus on the alleviation of distress and its prevention in order to reduce unnecessary suffering caused by depression or anxiety. Finally, studies could explore whether a combination of pharmacotherapy and psychotherapy can produce superior outcomes to either approach alone, or whether bio-psychosocial factors (e.g. site of ALS onset, comorbid cognitive impairment, and therapeutic modifi cations to account for physical/ communication defi cits) moderate the effectiveness of these approaches.

Strengths and limitations
To the authors ' knowledge, this systematic review is the fi rst to examine psychotherapy interventions for reducing distress or improving well-being in pwALS, and represents an update to previous reviews of pharmacotherapy in this population. A limitation is that a meta-analysis could not be conducted due to the small number of identifi ed studies and heterogeneity in clinical and research variables. A further limitation is that a partial rather than comprehensive search of grey literature was completed, and so this review may be subject to some publication bias. For example, authors/experts in the fi eld were not contacted about unpublished data, and other grey literature sources (45) were not searched. A more comprehensive search may have identifi ed more studies, although this may have introduced further bias as it has been noted that diffi cult-to-locate studies are often of lower methodological quality (46).

Conclusions
There is currently insuffi cient evidence to support the use of specifi c psychotherapy interventions for reducing distress or improving well-being in pwALS, and no evidence for pharmacotherapy. In the absence of such evidence it is tempting to extrapolate fi ndings from intervention studies in non-ALS populations to those with ALS. However, this should not be presumed as numerous factors may moderate the effectiveness of pharmacotherapy and/or psychotherapy in pwALS. Consequently, further research is urgently needed to examine how distress can be alleviated, how gains in distress reduction can be maintained, and how distress can be prevented or well-being can be enhanced in those living with the devastating consequences of ALS. their gratitude and thanks to all those authors who responded to queries about their studies, and to two anonymous reviewers for their helpful comments.

Declaration of interest:
The authors declare no confl icts of interest in this study.