Quantifying motivational deficits and apathy: a review of the literature.

European Neuropsychopharmacology (]]]]) ], ]]]–]]]

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Quantifying motivational deficits and apathy: A review of the literature Mark Weisera,n, George Garibaldib a

Departments of Psychiatry, Tel Aviv University and Sheba Medical Center, Israel F. Hoffman-La Roche AG, Basel, Switzerland

b

Received 29 June 2014; accepted 23 August 2014

1.

KEYWORDS

Abstract

Alzheimer's disease; Apathy; Assessment tools; Major depressive disorder; Parkinson's disease; Schizophrenia

Varying definitions of apathy in the published literature and a lack of a consensus regarding diagnostic criteria make the identification and quantification of apathy difficult in both clinical trials and clinical practice. The Apathy Evaluation Scale was developed specifically to assess apathy, but variations in the threshold values defined for clinically significant apathy diminish its use as a screening tool in clinical trials, although it has demonstrated sensitivity to changes in treatment in a number of studies. The Neuropsychiatric Inventory contains an Apathy subscale, which has been used to identify clinical trial populations (with a consistent threshold value) and measure changes following treatment. Few of the other assessment tools currently used in patients with neuropsychiatric disorders are specific for apathy or explore it in any depth, most have not been validated in the general population, do not have cut-off points representing clinically significant apathy, and its changes over time and in response to treatment. Further research is required to address these issues in order to facilitate the quantification of apathy and its natural history. Such research should be conducted with the aim of developing new, specific tools for use across neuropsychiatric disorders. & 2015 Published by Elsevier B.V.

Introduction and rationale

Apathy, in the context of patients with neuropsychiatric disorders, is the focus of an increasing number of clinical and observational studies, due to its negative impact on functioning and quality of life (Leroi et al., 2011; Konstantakopoulos et al., n Corresponding author. Tel.: +972 3 5303773; fax: +972 3 6358599. E-mail address: [email protected] (M. Weiser).

2011; Benito-Leon et al., 2012; Kuhlmei et al., 2013). While a range of assessment scales exists for screening and measurement of apathy, none are currently considered the ‘gold standard’ tool. Some are apathy-specific, e.g. the Apathy Evaluation Scale (AES), while others contain subscales or components relating to apathy, e.g. the Neuropsychiatric Inventory (NPI). These are reviewed and summarised here in the context of individuals with Alzheimer's disease (AD), Parkinson's disease (PD), schizophrenia and major depressive disorder (MDD), and in the general population (as selected on the basis of the quantity of literature available). Recommendations based upon

http://dx.doi.org/10.1016/j.euroneuro.2014.08.018 0924-977X/& 2015 Published by Elsevier B.V.

Please cite this article as: Weiser, M., Garibaldi, G., Quantifying motivational deficits and apathy: A review of the literature. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2014.08.018

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M. Weiser, G. Garibaldi

this review are made regarding applicability in both clinical practice and the clinical trial settings, and future research approaches are suggested.

2.

Experimental procedures

MEDLINEs as accessed through PubMeds was the sole database used in this review. Initial search terms were the following: (Apathy OR motivation OR motivational deficit OR avolition OR lassitude OR loss of interest) AND (rating scale OR assessment); (apathy OR motivation OR motivational deficit OR avolition OR lassitude OR loss of interest) AND (depression OR psychosis OR schizophrenia OR Alzheimer's disease OR dementia OR Parkinson's disease); (apathy OR motivation OR motivational deficit OR avolition OR lassitude OR loss of interest) AND (antidepressant OR antipsychotic OR neuroleptic OR anticholinergic OR antiparkinsonian OR dopaminergic). English language articles published up to September 2013 were selected, with no time limit for the earliest date of publication. Relevant citations within the publications identified via the searches were also reviewed. The full articles were analysed for the following information: (1) components relating to apathy/motivation; (2) validation and psychometric properties; (3) application in recent clinical studies (published 2011–2013). Secondly, the rating scales identified were themselves used as search terms to identify further relevant articles.

3. Apathy/motivation-focused assessment tools 3.1.

Tools used in the general population

Assessment tools for the investigation of apathy in the general population have largely been based on an evaluation of motivation along a continuum, from high to low. In general, they do not contain any defined cut-off values for lack of motivation (Vallerand et al., 1992; Pelletier et al., 1995). The Academic Motivation Scale (AMS) consists of seven subscales, covering intrinsic motivation, extrinsic motivation, and amotivation; each of which contain four items that the individual self-rates using a seven-point scale (Vallerand et al., 1992). The AMS was validated in university students, and showed adequate levels of internal consistency and test–retest reliability. The Sports Motivation Scale (SMS) is a comparable tool, with the exception that it focuses on students undertaking sporting activities (Pelletier et al., 1995). The 16-item Academic Amotivation Inventory (AAI) also rates the presence of motivation (Legault et al., 2006) and has been applied to school children. The AAI showed strong correlations with academic self-esteem, lack of academic interest, academic anxiety and indifference regarding academic achievement. The Intrinsic Motivation Inventory (IMI) is a comprehensive, self-rated, 54-item, six-subscale tool (Ryan, 1982; Choi et al, 2009). It focuses on the degree of motivation present in an individual, with ‘amotivation’ at the low end of the scale. It has demonstrated good psychometric properties.

3.2. Tools used in patients with neuropsychiatric disorders Some rating scales for use in neuropsychiatric disorders are available in alternative versions, for the clinician's objective assessment, the patient's subjective assessment and the caregiver's assessment. While the patient has the greatest experience of her/his emotional state, apathy may be associated with lack of insight, so a clinician's objective evaluation may be more valid than a patient's self-rating (Starkstein et al., 2001; Njomboro and Deb, 2012). A caregiver may also be able to provide a more accurate record of the frequency and duration of symptoms than the individual concerned. Interview of the patient by the clinician provides an opportunity to compare the caregiver's insights with the patient's perceptions (de Medeiros et al., 2010). The AES was specifically designed to provide a detailed exploration of the behavioural, cognitive and emotional aspects of apathy (Table 1) (Marin et al., 1991). Versions for the ratings of clinicians (AES-C), caregivers (AES-I) and patients (AES-S) are available, and a 10-item short version of the AES (AES-10) has been created specifically for use among nursing-home residents (Lueken et al., 2007). The AES was initially validated in individuals with AD, stroke, MDD and healthy elderly subjects (Marin et al., 1991). It demonstrated high inter-rater reliability and test–retest reliability; there was also a clear discrimination between apathy and depression, and apathy and anxiety on the AES-C and AES-S. Mean AES scores were also significantly higher for stroke, AD and MDD patients relative to control subjects. In another sample of patients with dementia, AES-S and AES-I total scores were weakly correlated with the depression subscale of the NPI, while AES-C total score was not correlated with NPI-Depression score (Clarke et al., 2007). The internal consistencies of the apathy factors in each scale were high. Threshold values of the AES total score have been proposed as indicators of clinically significant apathy. However, these have differed across studies, ranging from Z30 to Z41.5 (Marangell et al., 2002; Marin et al., 1991; Clarke et al., 2007; Cramer et al., 2010; Varanese et al., 2011; Raskin et al., 2012; Lenze et al., 2012; Clarke et al., 2008). To date no studies have reported discrete ranges for different severities of apathy or the determination of a minimal clinically important difference (MCID) in AES score, although changes in mean scores have indicated a sensitivity to treatment effects in AD, PD and MDD patients (Padala et al., 2010; Lam et al., 2012; Drapier et al., 2008; Marangell et al., 2002; Ravindran et al., 2008; Raskin et al., 2012; Lenze et al., 2012). Several factor analyses of the AES-C, AES-I and AES-S have been conducted in individuals with AD and other types of dementia, PD, MDD, stroke and subarachnoid haemorrhage, and psychosis. These studies identified two or three factors in the AES with varying terminologies, including interest; cognitivebehavioural; social indifference; insight and social contacts (Marin et al., 1991; Hsieh et al., 2012; Clarke et al., 2007; Ahearn et al., 2012; Faerden et al., 2008). One study has described an AES-apathy subscale, comprising 12 items from the original scale that all relate to interests, motivation and initiative, with clinically significant apathy defined as a score of Z27 (Faerden et al., 2008, 2009).


Quantifying motivational deficits and apathy: A review of the literature The Apathy Scale (AS) (Table 2) was derived from the AES, and in studies involving AD, PD and stroke patients it has demonstrated good discriminant validity between apathy and depression (Starkstein et al., 1992, 2001, 2005, 1993). A threshold score of Z 14 has generally been used in clinical studies to indicate the presence of clinically significant apathy (Starkstein et al., 1993; Kirsch-Darrow et al., 2011; Morley et al., 2011; Ziropadja et al., 2012; Ferencz et al., 2012; Leroi et al., 2011). Caregivers of AD patients rate the 16 items comprising the Dementia and Apathy Interview Rating (DAIR) scale (Table 2) (Strauss and Sperry, 2002). This tool has shown good inter-rater and test–retest reliability, and no significant correlation with depressive symptoms. The Lille Apathy Rating Scale (LARS) (Table 2) was chiefly designed for use in PD patients (Sockeel et al., 2006). It has demonstrated good psychometric properties, but has a complicated scoring system (Cubo et al., 2012; Raffard et al., 2013). A threshold score of 22 or higher is proposed to confirm the presence of clinically significant apathy (Ferencz et al., 2012; Cubo et al., 2012); the severity of apathy according to the LARS has also been defined (Sockeel et al., 2006). Notably, a study designed to validate diagnostic criteria for apathy in PD applied a threshold score of 16 or higher (Drijgers et al., 2010). A short form of the tool (12 items) has been developed for use in everyday clinical practice, and a Table 1

1 2 3b 4 5 6 7 8b 9 10b 11b 12 13b 14b 15b 16 17 18

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caregiver-rated version is also available (Dujardin et al., 2013, 2008). The Intrinsic Motivation Inventory for Schizophrenia Research (IMI-SR) was validated in patients with schizophrenia, where it was shown to be sensitive to the effects of therapeutic interventions (Table 2) (Choi et al., 2009). Test–retest reliability was good and discriminant validity in comparing values with normal control subjects was high. One study using the IMI-SR has recently been reported (Tas et al., 2012). The Apathy Inventory (AI) and the Motivation and Energy Inventory (MEI) (Table 2) were designed as assessment tools for use in AD/PD and MDD patients, respectively (Robert et al., 2002; Fehnel et al., 2004). However, their use in clinical studies has been limited.

4. Assessment tools with components or items evaluating apathy 4.1.

Neuropsychiatric Inventory (NPI)

The NPI (Table 3) was developed for use in patients with dementia (Cummings et al., 1994; Cummings, 1997). It is based on responses from a structured interview with caregivers and was validated against normal control subjects. The apathy

The Apathy Evaluation Scale: items and factor structure (adapted from Marin et al. (1991)).

Item

Positive or negative Factor syntax type

S/he is interested in things S/he gets things done during the day Getting things started on his/her own is important to him/her S/he is interested in having new experiences S/he is interested in learning new things S/he puts little effort into anything S/he approaches life with intensity Seeing a job through to the end is important to him/her S/he spends time doing things that interest him/her Someone has to tell him/her what to do each day S/he is less concerned about her problems than s/he should be S/he has friends Getting together with friends is important to her/him When something good happens, s/he gets excited S/he has an accurate understanding of his/her problems Getting things done during the day is important to him/her S/he has initiative S/he has motivation Scored from 1 (not at all true) to 4 (very true)

+ + +

C B C

+ + + +

C C B E C

+

B

Patient selfevaluation items

✓

Quantifiable itemsa ✓ ✓

✓ ✓

✓

B C + +

B C

+

E

+

O

+

C

+ +

O O

✓

✓

✓

Item is rated by counting the number of instances cited by the patient for a particular item (not at all =0 items; slightly=1–2 items; somewhat=2–3 items; very=3 or more items); B=behavioural; C=cognitive; E =emotional; O=other. b Item has non-significant correlation (Pearson's r) with the Hamilton Rating Scale for Depression. a


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Table 2

Summary of apathy-specific rating scales.

Scale

Components and scoring

Psychometric properties

Usage

Studies published between January 2011 and September 2013

Apathy Inventory (AI) (Robert et al., 2002)

Three items: emotional blunting, lack of initiative, lack of interest Caregiver version Each item is scored for frequency (1 4) and severity from 1 (mild) to 3 (severe) Total score =frequency severity scores Patient version Each item is scored using a Likert-type scale from 1 (mild) to 12 (severe)

Validated in AD, PD and MCI patients and healthy elderly subjects (n =115) Caregiver version Internal consistency (CA): 0.84 Inter-rater reliability (KC): 0.99 Test–retest reliability (KC): emotional blunting (0.99), lack of initiative (0.97), lack of interest (0.99), total score (0.99) Correlation with NPIDysphoria score: lack of initiative (r=0.32; po0.05), lack of interest (r =0.4; po0.001), total score (r=0.37; po0.01) Correlation with NPI-Apathy score: lack of initiative (r =0.23; po0.01), lack of interest (r =0.63; po0.001) Patient version Correlation with NPIDysphoria score: lack of initiative (r=0.37; po0.01), lack of interest (r =0.31; po0.05), total score (r=0.42; po0.001) No significant correlations with NPI-Apathy score

Caregiver- and patient-rated versions containing the same three items

12-week, randomised, double-blind study of piribedil vs. placebo in PD patients (n =37) with AS score Z14 at baseline; change from baseline in AI: improvement of 46.6% with piribedil vs. worsening of 2.3% with placebo (p=0.005) (Thobois et al., 2013)

Apathy Scale (AS) 14 Items: interest (2 items), (Starkstein et al., concern, doing efforts, 1992) seeking something to do, plans for the future, motivation, energy, need to be told what to do each day, indifference, unconcerned with many things, push to get started, emotional blunting, apathetic Each item is rated from 0 (not at all) to 4 (a lot) Maximum score of 42; proposed threshold of Z14 to identify clinical apathy

Validated in PD patients (n =50) Internal consistency (CA): 0.76 Inter-rater reliability: r= 0.81 Test–retest reliability: r= 0.90

Clinician Cohort study in PD patients interview with with AS score Z14 (n =26) patient and healthy controls (n =38); mean AS score: 46.57711.9 vs. 21.6874.78 (po0.001) (Leroi et al., 2011) 12-week, randomised, double-blind study of piribedil vs. placebo in PD patients (n =37) with AS score Z14 at baseline; decrease from baseline in AS: 34.6% vs. 3.2% (p=0.015) (Thobois et al., 2013)

Dementia Apathy Interview and Rating (DAIR) scale (Strauss et al., 2012)

Validated in caregivers of AD patients (n =100) Internal consistency (CA): 0.89 Test–retest reliability: r= 0.85

Clinician Randomised, single-blind, interview with crossover study in dementia primary patients (n =146) caregiver comparing structured activities with patientselected activities;

Scored from 0 (almost never) to 3 (almost always) and then change from before memory loss was apparent; score =sum of all items


Quantifying motivational deficits and apathy: A review of the literature

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Table 2 (continued ) Scale



Usage

reflecting change/number of Divergent validity: no items completed significant correlation between DAIR total score and dysphoria (r =0.08) Significant correlations with MMSE total score (r= 0.36; pr0.001), Clinical Dementia Rating (r=0.40; pr 0.001)

Studies published between January 2011 and September 2013 intervention vs. control periods: treatment difference of 0.21 (95% CI, 0.07 0.34; po0.005) (Ferrero-Arias et al., 2011)

The Intrinsic Motivation Inventory for Schizophrenia Research (IMI-SR) (Choi et al, 2009)

Validated in schizophrenia patients and healthy control subjects (n =95) Mean total score significantly different for schizophrenia patients vs. controls (61.14716.83 vs. 89.2779.26; p=0.03) Internal consistency (CA): total score (0.86), interest/ enjoyment, (0.95), choice (0.89), value/usefulness (0.91), effort (0.70), pressure/tension (0.54) Test–retest reliability: total score (r=0.77), interest/ enjoyment (r =0.74), choice (r =0.76), value/usefulness (r =0.70), effort (r= 0.68), pressure/tension (r=0.25) No correlation between IMISR and BPRSnegative symptoms subscale score Sensitive to treatment effects: intervention group (t =0.619; p =0.011), control group (t=1.25; p=0.213)

Interest/enjoyment Patient selfdomain rated 1. I enjoyed doing this activity very much2. This activity was fun to do3. I think this is a boring activity4. I would describe this activity as very interesting5. I thought this activity was quite enjoyable6. I was thinking about how much I enjoyed it7. This activity does not hold my attention at allValue/usefulness1. I believe this activity could be of some value to me2. I think that doing this activity is useful3. I think this is important to do4. I would be willing to do this again5. I think doing this activity could help me6. I think this is an important activity

Cohort study of patients with remitted schizophrenia (n =32) undergoing cognitive training; interest/ enjoyment scores for learners vs. non-learners: 32.6779.00 vs. 36.9377.00 (p =0.034); value/usefulness scores for learners vs. non-learners: 30.17710.89 vs. 41.0079.07 (p =0.019) (Tas et al., 2012)

Lille Apathy Rating (LARS) Scale (Sockeel et al., 2006)

33 Items in nine domains: everyday productivity, lack of interest, lack of initiative, extinction of noveltyseeking, motivation, blunting of emotional response, lack of concern, poor social life, extinction of self-awareness

Validated in PD patients and healthy control subjects (n =217) Internal consistency (CA): between items (0.80), between subscales (0.74) Inter-rater reliability: r =0.98

Cross-sectional study of schizophrenia patients and healthy control subjects (n =50); mean LARS total score: schizophrenia patients vs. controls ( 15.12713.51 vs.

Clinician; structured interview with patient


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M. Weiser, G. Garibaldi Table 2 (continued ) Scale



First three items scored using a Likert-type scale from 1 to 5; remainder of items scored as yes/no Total score ranges from 36 to +36; proposed clinical apathy threshold of 22 or higher; mild apathy ( 21 to 17); moderate apathy ( 16 to 10); severe apathy ( 9 to +36)

Test–retest reliability: r= 0.95 Correlation between LARS total score and AES total score: r=0.87

Motivation and Validated in MDD patients Energy Inventory (n =809) (MEI) (Fehnel et al., 2004) Internal consistency (CA): mental energy (0.87), social motivation (0.82), physical energy (0.75) Correlations between mental energy score and HDRS fatigue/somatic symptoms score (r = 0.13; po0.05), mental energy score and HDRS physical energy score and HDRS work/loss of interest score (r = 0.15; po0.05), social motivation score and HDRS work/loss of interest score (r = 0.11; po0.05), physical energy score and HDRS fatigue/ somatic symptoms score (r = 0.31; po0.05) Sensitive to treatment effects: antidepressant A vs. placebo for physical energy score (t =2.65; p =0.008), antidepressant B vs. placebo for mental energy score (t=2.51; p=0.013), antidepressant B vs. placebo for social motivation score (t=2.10; p=0.036)

Mental energy 3. Trouble getting out of bed 5. Trouble finishing things 10. Trouble making decisions 13. Focusing attention Social motivation 23. Interest in new tasks 24. Interest in new things 25. Interest in new people 26. Interest in talking to others 37. Interest in social activities Physical energy 1. Began day enthusiastic 18. Felt motivated

Usage

Studies published between January 2011 and September 2013 27.2075.22; p=0.0001) (Raffard et al., 2013)

Patient selfrated

None

AD, Alzheimer's disease; BPRS, Brief Psychiatric Rating Scale; CA, Cronbach's alpha; CI, confidence interval; HDRS, Hamilton Depression Rating Scale; KC, kappa coefficient; MCI, mild cognitive impairment; MDD, major depressive disorder; MMSE: Mini Mental State Examination; NPI, Neuropsychiatric Inventory; PD, Parkinson's disease Data values are mean 7 standard deviation unless otherwise stated.

subscale (NPI-Apathy) comprises a screening question and then eight further items if the response to the screening question is positive. Frequency and severity of symptoms are rated, in addition to caregiver distress (Cummings, 1997, 2009). Two separate studies have compared AES-10 and NPI-Apathy scores in elderly nursing-home residents (Lueken et al., 2007; Leontjevas et al., 2012), finding a moderate correlation.

The scoring for NPI-Apathy ranges from 0 (absent) to 12 (severe and very often present), demonstrating the ability to measure both severity and frequency (Cummings et al., 1994; Cummings, 1997). In studies involving healthy elderly individuals, and those with AD, PD, MDD, schizophrenia or MCI, clinically significant apathy has generally been defined as NPIApathy scores greater than 3 or 4 (Onyike et al., 2007; Mulin


Quantifying motivational deficits and apathy: A review of the literature et al., 2011; Vialta-Franch et al., 2013;Waldemar et al., 2011). An ongoing clinical trial assessing the effects of methylphenidate on apathy in AD patients has defined clinical apathy based on the NPI-Apathy subscale as: (1) frequency of apathy is ‘very frequently’; or (2) the frequency of apathy is ‘frequently’ or ‘often’, and the severity of the apathy is ‘moderate’, or ‘marked’ (Drye et al., 2013). This approach takes into account the fact that some patients may have more frequent but less severe symptoms, or less frequent but more severe symptoms. The NPI-Apathy subscale score has demonstrated sensitivity to treatment effects in a number of studies involving patients with AD (Gauthier et al., 2002; Ferrero-Arias et al., 2011; Rosenberg et al., 2013). It has been proposed (in different studies) that a Z 4-point or Z30% decrease in NPI total and subscale scores is a clinically relevant change (Mega et al., 1999; Cummings et al., 2001), but this approach has not been widely adopted. A nursing-home version of the NPI (NPI-NH) is available for use in institutional settings (Wood et al., 2000), and a brief version was designed for everyday clinical use and is self-rated by caregivers (NPI-Q) (Kaufer et al., 2000). A clinician-rated expanded version of the NPI (NPI-C) has also been developed (de Medeiros et al., 2010).

4.2. Other rating scales with components addressing apathy in neuropsychiatric patients There is a wealth of other assessment tools that contain components which may be considered proxies for apathy. These are discussed briefly below and their key characteristics and recent application are summarised in Table 4. The Frontal Systems Behaviour Scale (FrSBe) encompasses apathy, disinhibition and executive function and was designed for use in neurodegenerative diseases and traumatic brain injury (Grace and Malloy, 2001; Stout et al, 2003). It has been validated in patients with schizophrenia and healthy control subjects as well as AD patients, and its apathy subscale is sensitive to treatment effects in AD and PD patients (Velligan et al., 2002; Norton et al., 2001; Frakey et al., 2012; Marsh et al., 2009; Denheyer et al., 2009). Three other tools with components specifically evaluating apathy in patients with PD are available – the Non-Motor Symptoms Questionnaire (NMSQuest), the Non-Motor Symptoms Scale (NMSS) (Chaudhuri et al., 2006, 2007; Rios-Romenets et al., 2012; Martinez-Martin et al., 2009) and the non-motor symptoms section of the Unified Parkinson's Disease Rating Scale (UPDRS) (Pedersen et al., 2008). The patient self-rated NMSQuest has a single item covering apathy/loss of interest, while the clinician-rated NMSS contains a mood/cognition subscale with two items relating to loss of interest. The nonmotor symptoms section of the UPDRS contains a single item assessing apathy. However, in the validation study, its sensitivity and specificity for identifying apathy compared with the AS were only moderate (Pedersen et al., 2008). The Brief Psychiatric Rating Scale (BPRS) is an established tool that has been used to measure symptoms in psychosis and MDD patients (Overall and Gorham, 1962; Ventura et al., 1993). Numerous factor analyses have been performed, with the identification of different subscales encompassing apathy making it difficult to compare findings across studies (Ventura et al., 2000; Biancosino et al., 2010; Zanello et al., 2013). Two recent

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studies using a BPRS-Apathy subscale have reported treatmentrelated changes in patients with schizophrenia and MDD (Miyaoka et al., 2012; Zanello et al., 2013). The most widely-used assessment tool for individuals with schizophrenia participating in clinical trials is the Positive and Negative Syndrome Scale (PANSS), a clinician-rated tool that obtains information from the patient, caregiver and clinical staff managing the patient (Kay et al., 1987). The PANSS has demonstrated high levels of internal consistency, and test– retest reliability. The negative symptoms and general psychopathology subscales contain items assessing emotional withdrawal, passive-apathetic social withdrawal, and disturbance of volition, which may be considered indicators of apathy. However, there are no studies in patients with schizophrenia reporting results specifically for these items. The Scale for Assessment of Negative Symptoms (SANS) is used by clinicians specifically to evaluate the presence and severity of negative symptoms in individuals with schizophrenia (Andreasen, 1982). The SANS-avolition-apathy subscale contains four items and a global rating of apathy, and has demonstrated good psychometric properties. A number of clinical trials have demonstrated a sensitivity to change with the SANS following treatment in patients with predominant negative symptoms (Zoccali et al., 2004; Alvarez et al., 2006; Grant et al., 2012; Lyne et al., 2012; Stauffer et al., 2012). The Schedule for the Deficit Syndrome (SDS) was also devised in order to identify individuals with schizophrenia who have predominant negative symptoms (Kirkpatrick et al., 1989). It has demonstrated good inter-rater reliability and has been used in many studies, although none published recently. The avolition subscale score is correlated with PANSS negative symptoms subscale score and also the PANSS items emotional withdrawal and passive–apathetic social withdrawal (Nakaya and Ohmori, 2008). Problems with communication, emotion/affect, social involvement, motivation, cognition and retardation can also be assessed using the Negative Symptom Assessment (NSA-16) (Alphs et al., 1989; Axelrod et al., 1993). However, although the NSA-16 contains motivation as a distinct item, this term is not specifically defined. A shorter, four-item version of the NSA has been validated in patients with predominantly negative symptoms of schizophrenia (Alphs et al., 2010, 2011). Both versions of the NSA were strongly correlated with SANS total score. Two separate quality of life scales have been developed for use in patients with schizophrenia. The Schizophrenia Quality of Life Scale (SQLS) contains a motivation/energy subscale (Wilkinson et al., 2000), and has shown reasonable internal consistency and sensitivity to treatment in patients with schizophrenia (Kitajima et al., 2012). The Intrapsychic Foundations subscale of the Quality of Life Scale (QLS) contains the items purpose, motivation and curiosity, and has been shown to identify the effects of treatment (Heinrichs et al., 1984; Rosenheck et al., 2011). More recently, two scales have been developed with an emphasis on utility in clinical trials (Kirkpatrick et al., 2011; Horan et al., 2011). These cover the five National Institute of Mental Health – Measurement and Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS) consensus domains, one of which is avolition. The Brief Negative Symptom Scale (BNSS) is rated by clinicians, whereas the Clinical Assessment Interview for Negative Symptoms (CAINS) is self-rated by


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Table 3 The Neuropsychiatric Inventory Apathy domain (adapted from Cummings et al. (1994) and Cummings, 1997, 2009). Behaviour during the preceding 4 weeks Screening Has the patient lost interest in the world question(s) around him/her? Has he/she lost interest in doing things or does he/she lack motivation for starting new activities? Is he/she more difficult to engage in conversation or in doing chores? Is the patient apathetic or indifferent? If yes to the above

Scoring

1. Does the patient seem less spontaneous and less active than usual? 2. Is the patient less likely to initiate a conversation? 3. Is the patient less affectionate or lacking in emotions when compared to his/her usual self? 4. Does the patient contribute less to household chores? 5. Does the patient seem less interested in the activities and plans of others? 6. Has the patient lost interest in friends and family members? 7. Is the patient less enthusiastic about his/her usual interests? 8. Does the patient show any other signs that he/she doesn't care about doing new things? Frequency 1. Rarely – less than once per week 2. Sometimes – about once per week 3. Often – several times per week but less than every day 4. Very often – once or more per day or continuously Severity 1. Mild – apathy is notable but produces little interference with daily routines; only mildly different from patient's usual behaviour; patient responds to suggestions to engage in activities 2. Moderate – apathy is very evident; may be overcome by the caregiver with coaxing and encouragement; responds spontaneously only to powerful events such as visits from close relatives or family members 3. Severe – apathy is very evident and usually fails to respond to any encouragement or external events Caregiver distress How emotionally distressing do you find this behaviour? 0. Not at all 1. Minimally (almost no change in work routine)

Table 3 (continued ) Behaviour during the preceding 4 weeks 2. Mildly (almost no change in work routine but little time rebudgeting required) 3. Moderately (disrupts work routine, requires time rebudgeting) 4. Severely (disruptive, upsetting to staff and other residents, major time infringement) 5. Very severely or extremely (very disruptive, major source of distress for staff and other residents, requires time usually devoted to other residents or activities) Though frequency is rated on a 1 4 scale there is also the option of rating absent = 0. The overall rating (severity frequency) is based on that behaviour identified by the sub-question as being the most aberrant and is therefore based on a single score of 0 12 for each domain Caregiver distress score is separate

patients. The BNSS focuses directly on lack of interest in behaviours, while CAINS explores patients' experiences of motivation and emotion, as well as the frequency of their actual engagement in relevant activities. In schizophrenia patients, both scales demonstrated good internal consistency, inter-rater reliability and test–retest reliability, in addition to good discriminant validity when compared with depression rating scales (Kirkpatrick et al., 2011; Horan et al., 2011). The BNSS-avolition subscale score has also demonstrated a significant correlation with SANS-avolition-apathy score (Kirkpatrick et al., 2011; Strauss et al., 2012), while in one published study the motivation/pleasure subscale score of the CAINS was significantly correlated with both BPRS negative symptom subscale score and SANS total score (Kring et al., 2013). Two scales, the Premorbid Adjustment Scale (PAS) and the Symptom Onset in Schizophrenia (SOS) inventory, have been designed to assess prodromal symptoms retrospectively in young people at around 6 months prior to their first hospitalisation or contact with psychiatric care services (Cannon-Spoor et al., 1982; Perkins et al., 2000). The sociability and withdrawal item of the PAS seeks to explore the extent to which an individual is motivated to seek opportunities to socialise. The PAS has demonstrated good internal consistency, high test– retest reliability and discriminant validity when comparing psychiatric inpatients and healthy controls (Krauss et al., 1998; Morice et al., 1985; Shapiro et al., 2009). However, the 6-month time frame of the PAS assumes an abrupt recent change in behaviour rather than the generally insidious nature of symptom onset (van Mastrigt and Addington, 2002), and its use has not been reported recently. The four categories in the SOS encompass general prodromal symptoms, negative symptoms (including avolition), positive symptoms, and disorganised symptoms. When applying these criteria to a sample of



9

Table 4 Summary of assessment tools with components used to assess apathy co-morbid to neuropsychiatric disorders: psychometric properties and application. Scale


Components approximating apathy

Usage

Studies reporting apathy outcomes published between January 2011 and September 2013

Brief Negative Symptom Scale (BNSS) (Strauss et al., 2012)

Validated in schizophrenia or schizoaffective disorder patients (n =100) Internal consistency (CA): 0.94 for total score Test–retest reliability: avolition-behaviour item (r =0.86; po0.001), avolition-inner experience item (r =0.91; po0.001) Convergent validity: BNSS total score correlated with SANS total score (r=0.8; po0.001), BPRS negative symptoms subscale score (r =0.68; po0.001). Avolition subscale score correlated with SANSAvolition/apathy subscale score (r= 0.66; po0.001) Discriminant validity: BNSS total score not correlated with BPRS positive symptoms score (r = 0.06) or BPRS disorganisation symptoms (r =0.04)

Avolition items 1. Avolition behaviour 2. Avolition inner experience

Clinician; semiValidation study only structured interview with patient

Factor analysis in Brief Psychiatric Rating Scale (BPRS) patients with MDD (Biancosino et al., (n =163) 2010) Psychometric properties not reported

Clinician Apathy subscale 1. Emotional withdrawal 2. Motor retardation 3. Blunted affect

6-week open-label singlearm study of adjunctive minocycline in psychotic depression patients (n =25); statistically significant improvement from baseline to 6 weeks reported for BPRS item emotional withdrawal (po0.001) (Miyaoka et al., 2012)

24-item expanded BPRS (Zanello et al., 2013)

Apathy subscale Clinician 1. Blunted affect 2. Emotional withdrawal 3. Motor retardation 4. Unco-operativeness

Validation study only

Factor analysis in patients with MDD (n =240) Sensitive to treatment effects: change from hospital admission to discharge in mean apathy factor score: 1.6370.69 vs. 1.4070.48 (p=0.007)


10




Clinical Assessment Interview for Negative Symptoms (CAINS) (Kring et al., 2013)

Validated in patients with schizophrenia or schizoaffective disorder (n =162) Motivation/pleasure subscale internal consistency (CA): 0.76 Motivation/pleasure subscale inter-rater reliability: 0.93 Motivation/pleasure subscale test–retest reliability: r =0.69 Motivation/pleasure subscale convergent validity: BPRS negative symptoms (r =0.28; po0.01), SANSAvolition/apathy subscale score (r =0.38; po0.01) Discriminant validity: BPRS depression symptoms (r=0.06), CDSS (r=0.13)

Motivation/pleasure Clinician; structured Validation study only items interview with 1. Recreation: motivation patient 2. Vocation: motivation

Clinical Positive Affect Scale (CPAS (Nierenberg et al., 2012)

Validated in college students (n =300)

Motivation items 1. Want to get things done Internal consistency (CA): 2. Feel motivated 0.97 Divergent validity: correlation with BDI (r= 0.68), BAI (r= 0.57)

Patient self-rated

Validation study only

Frontal Systems Behaviour Scale (FrSBe) (Velligan et al., 2002; Stout et al., 2003)

Apathy subscale 1. Speaks only when spoken to 8. Lacks initiative, motivation Apathy subscale internal 11. Neglects personal consistency (CA): 0.88 hygiene 14. Does nothing 16. Incontinence Apathy subscale test– 21. Lost interest in things retest reliability: r =0.68 23. Does not finish things (po0.0001) 24. Unconcerned and unresponsive Mean apathy subscale 29. Lacks energy scores: 21.9476.16 for 38. Is interested in sex schizophrenia patients 39. Cares about vs. 39.2679.08 for appearance controls (po0.0001) 41. Gets involved spontaneously

Clinician; structured interview with patient or caregiverrated

8-week randomised double-blind placebocontrolled study in AD patients (n =23) comparing modafinil with placebo; FrSBe-Apathy subscale scores at baseline: 95.64710.79 vs. 88.91711.95; FrSBeApathy subscale scores at 8 weeks: 89.0979.61 vs. 82.09713.52 (p=not significant) (Frakey et al., 2012)

Validated in schizophrenia patients and healthy controls (n =182)

Usage




11




Usage


t-score Z 65 proposed as 42. Does things without threshold for clinically reminders significant apathy 46. Starts conversations Hamilton Depression Validated in MDD patients Rating Scale (HDRS) (n =70) (Hamilton, 1960) Inter-rater reliability: r=0.90

Work and loss of interest Clinician; semiCohort study of PD item structured interview patients (n =48), divided with patient into apathy AES Z38) 0. No difficulty and no apathy (AES 1. Thoughts and feelings o38); positive of incapacity, fatigue or correlation between AES weakness related to score and HDRS work and activities, work or loss of interest item hobbies (p=0.022) (Varanese 2. Loss of interest in et al., 2011) activity, hobbies or work – either directly reported by the patient or indirect in listlessness, indecision and vacillation (feels he/ she has to push self to work or activities) 3. Decrease in actual time spent in activities or decrease in productivity. Rate 3 if the patient does not spend at least three hours a day in activities (job or hobbies) excluding routine chores 4. Stopped working because of present illness. Rate 4 if patient engages in no activities except routine chores, or if patient fails to perform routine chores unassisted

Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) (Fava et al., 2009)

Motivation items 1. Motivation/interest/ enthusiasm 3. Energy

Validated in MDD and generalised anxiety patients (n =150) Internal consistency (CA): motivation/interest/ enthusiasm item (0.66), energy item (0.81) Test–retest reliability: r=0.83 (po0.001) Convergent validity: MGH-CPFQ total score correlated with AES total score at baseline (r = 0.304; p=0.036) and following treatment (r = 0.304; p=0.036) Sensitivity to change: adjunctive to antidepressant treatment, change from

Patient self-rated

None


12




Usage


baseline in MGH-CPFQ total score (t =6.9; po0.001) Montgomery-Asberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979)

Validated in patients with MDD (n =64) Inter-rater reliability: baseline (r=0.89; po0.001), during treatment (r =0.95; po0.001), treatment difference (r=0.90; po0.001)

Lassitude item Clinician; semi6-week, randomised, 0. Hardly any difficulty in structured interview double-blind study with patient comparing amitifadine getting started. No versus placebo in MDD sluggishness patients (n =63); 2. Difficulties in starting significantly greater activities improvement from 4. Difficulties in starting baseline in MADRS simple routine activities anhedonia factor score which are carried out (apparent sadness, with effort reported sadness, 6. Complete lassitude. concentration Unable to do anything difficulties, lassitude, without help inability to feel) for amitifadine versus placebo (p=0.049) (Tran et al., 2012)

Negative Symptom Assessment-16 (NSA-16) (Axelrod et al., 1993)

Not reported

Loss of interest/ Clinician; structured None motivation subscale interview with 1. Poor grooming and patient hygiene 2. Reduced sense of purpose 3. Reduced hobbies and interests 4. Reduced daily activity

Non-motor Symptoms Questionnaire (NMSQuest) (Chaudhuri et al., 2006; RiosRomenets et al., 2012)

Validated in PD patients (n =123) and healthy control subjects (n= 96) Mean NMSQuest score =9.5 for PD patients vs. 4.0 for controls (po0.0001) Validated in PD patients (n =70) Apathy item sensitivity: 49% Apathy item specificity: 87% Apathy item positive predictive value: 75% Apathy item negative predictive value: 67%

Apathy/loss of interest item

Non-motor symptoms scale (NMSS) (Martinez-Martin et al., 2009)

Validated in PD patients (n =411) Mood/cognition subscale internal consistency (CA):

Mood/cognition subscale Clinician; semiNone 7. Has the patient lost structured interview interest in his/her with patient surroundings? 8. Has the patient lost interest in doing things or

Patient self-rated

Longitudinal study in PD patients receiving subthalamic DBS (n =24); Patients with apathy/loss of interest: 41.7% at baseline vs. 25% at 1 year (Nazzaro et al., 2011)



13




Usage


Clinician; semistructured interview with patient, plus input from caregiver and healthcare professional

10-year follow-up study of patients with FEP (n =178); PANSS items N2 and N4 were significantly correlated with AES-SApathy score at 10 years but not at baseline. Severity of apathy remained stable over time (Evensen et al., 2012)

Clinician; interview with patient, plus input from patient, caregiver and healthcare professional

None

Mood/cognition subscale lack motivation to start new activities? test–retest reliability 9. Does the patient feel (ICC): nervous, worried or frightened from no apparent reason? 10. Does the patient seem sad or depressed or has he/she reported such feelings? 11. Does the patient have flat moods without the normal highs and lows? 12. Does the patient have difficulty in experiencing pleasure from their usual activities or report that they lack pleasure? Negative symptoms subscale 2. Emotional withdrawal 4. Passive-apathetic social Internal consistency withdrawal (item vs. total scale; CA): General emotional withdrawal psychopathology (0.78; po0.001), subscale passive-apathetic social 7. Motor retardation withdrawal (0.79; 13. Disturbance of po0.001), motor volition retardation (0.27; 16. Active social po0.01), disturbance of avoidance volition (0.66; po0.001), active social avoidance (0.43; po0.001) Test–retest reliability: positive subscale (r =0.80; po0.001), negative subscale (0.68; po0.01), general psychopathology subscale (0.60; po0.02)

Positive and Negative Validated in patients with schizophrenia (n= 101) Syndrome Scale (PANSS) (Kay et al., 1987)

Premorbid Assessment Scale (PAS) (Cannon-Spoor et al., 1982)

Patients with schizophrenia and healthy control subjects (n =162) Correlations with duration of hospitalisation, age at onset and type of onset (insidious or acute)

Sociability and withdrawal item 0. Not withdrawn, actively and frequently seeks out social contacts 2. Mild withdrawal, enjoys socialisation when involved, occasionally seeks opportunities to socialise 4. Moderately withdrawn, given to day


14




Usage


dreaming and excessive fantasy, may passively allow self to be drawn into contact with other but does not seek it 6. Unrelated to others, withdrawn and isolated. Avoids contacts Quality of Life Scale (Heinrichs et al., 1984)

Validated in patients with Intrapsychic foundations Clinician; semiOpen-label randomised schizophrenia (n =52) subscale structured interview study in schizophrenia with patient patients (n =382) 13. Purpose comparing oral 14. Motivation antipsychotic of 15. Curiosity physician's choice and Inter-rater reliability long-acting injectable (ICC): intrapsychic risperidone; mean foundations subscale intrapsychic foundations (0.91), sense of purpose subscale score: (0.87), motivation (0.80), 3.2470.06 vs. curiosity (0.81) 3.1470.06; treatment difference: 0.1070.08; p=0.18 (Rosenheck et al., 2011)

Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1982)

Validated in patients with Avolition/apathy schizophrenia (n =26) subscale 1. Grooming and hygiene Internal consistency for 2. Impersistence at work individual items vs. or at school Avolition/apathy 3. Physical anergia subscale (CA): grooming 4. Subjective complaints and hygiene (0.68), of avolition-apathy impersistence at work or 5. Global rating of at school (0.75), physical avolition-apathy anergia (0.70), subjective complaints of avolition-apathy (0.27), global rating of avolitionapathy (0.91) Internal consistency vs. SANS total score (CA): grooming and hygiene (0.54), impersistence at work or at school (0.47), physical anergia (0.60), subjective complaints of avolition-apathy (0.19), global rating of avolitionapathy (0.71), Avolition/ apathy subscale (0.74)

Clinician; interview with patient, plus input from patient, caregiver and healthcare professional

Cohort study in patients with first-episode schizophrenia spectrum disorders (n= 333); avolition-apathy subscale score and relationships with friends/peers item score Z3 was a significant predictor of MDD, delusional disorder, brief psychotic disorder, substance-induced psychotic disorder, but not bipolar disorder (Lyne et al., 2012) Study comparing patients with predominant negative symptoms or prominent negative symptoms of schizophrenia (n =343) receiving olanzapine or quetiapine; mean Avolition-apathy subscale scores at baseline: 7.073.2 vs. 7.673.0 (p=0.067). Change from baseline to 24 weeks was comparable for both groups (Stauffer et al., 2012)



15




Usage

Studies reporting apathy outcomes published between January 2011 and September 2013 18-month, randomised, single-blind study in lowfunctioning schizophrenia patients (n =60) receiving cognitive therapy (CT) +standard therapy (ST) vs. ST alone; change from baseline in avolitionapathy was significantly superior for CT +ST vs. ST at all timepoints during the study (Grant et al., 2012) Randomised double-blind study of repeated TMS vs. sham procedure in schizophrenia patients (n =40) with predominant negative symptoms; mean change in SANSAvolition/apathy subscale score: 44.46733.81 % vs. 8.62737.86% (po0.01) (Prikryl et al., 2013)

Schedule for the Deficit Syndrome (SDS) (Kirkpatrick et al., 1989; Kimhy et al., 2006)

Validated in patients with schizophrenia (n= 40) Inter-rater reliability: total scale (0.73), curbing of interests (0.66), diminished sense of purpose (0.69), diminished social drive (0.60)

Avolition subscale Clinician interview 1. Curbing of interests with patient 2. Diminished sense of purpose 3. Diminished social drive

None

Schizophrenia Quality of Life Scale (SQLS) (Wilkinson et al., 2000)

Internal consistency (CA): lacking energy (0.63), can't be bothered to do things (0.64), able to carry out daily activities (0.67), take part in enjoyable activities (0.76), planning ahead (0.60), tend to stay home (0.59)

Motivation/energy Patient self-rated subscale 1. I lack the energy to do things 6. I can't be bothered to do things 12. I am able to carry out daily activities 13. I take part in enjoyable activities 15. I like to plan ahead 17. I tend to stay at home and do not go out

Patients with schizophrenia (n=20) discontinuing benzodiazepine treatment while remaining on secondgeneration antipsychotics; change from baseline in mean motivation/energy subscale score: 7.1079.48 (p=0.003) (Kitajima et al., 2012)

Construct validity: significant correlations between motivation/ energy subscale score and HADS-anxiety (r =0.54; po0.001) and HADS-depression (r =0.68; po0.010) subscale scores


16




Usage

Social Adaptation Self-evaluation Scale (SASS) (Bosc et al., 1997)

Validated in patients with MDD and a sample of the general population (n =3912) Internal consistency (CA): job interest (0.74), homework interest (0.74), interest in hobbies (0.73), familyseeking behaviour (0.74), relationship-seeking behaviour (0.72), social inquisitiveness (0.73), intellectual interest (0.73) Test–retest reliability: mean SASS scores 41.976.5 vs. 42.276.6 (p40.05) Divergent validity: no significant correlation with HDRS total score

Items across subscales Patient self-rated 1. Job interest 2. Homework interest 4. Interest in hobbies 6. Family-seeking behaviour 9. Relationship-seeking behaviour 15. Social inquisitiveness 16. Intellectual interest

None

Symptom Onset in Schizophrenia (SOS) inventory (Perkins et al., 2000)

Patients with schizophrenia, schizoaffective disorder or schizophreniform disorder (n=35) Inter-rater reliability (KC): presence of symptoms (r =0.88), duration of symptoms (r=0.97)

Negative symptoms subscale 1. Social withdrawal 2. Avolition 3. Decreased expression 4. Decreased experience of emotions

Cohort study in FEP patients (n =77); mean duration of untreated SOS negative symptoms subscale score: 13.73 months (Cuesta et al., 2012)

Unified Parkinson's Disease Rating Scale Section I (Pedersen et al., 2008; Gallagher et al., 2012)

Validated in patients with Motivation/initiative Clinician; structured None PD (n =94) item interview with 0. Normal patient Internal consistency (CA): 1. Less assertive than 0.85 usual; more passive Validated in PD patients 2. Loss of initiative or (n =58) disinterest in elective (non-routine) activities Significant correlation 3. Loss of initiative or between motivation/ disinterest in day-to-day initiative item and AS(routine) activities defined apathy (Pearson: 4. Withdrawn, complete 0.27; p=0.037) loss of motivation Significant correlation between motivation/ initiative item and MADRS total score (Pearson: 0.62; po0.005) Threshold apathy screening score of 1/2: sensitivity (70%),

Clinician; structured interview with patient, plus input from patient, caregiver and healthcare professional




17




Usage


specificity (75%), positive predictive value (37%), negative predictive value (92%) AES, Apathy Evaluation Scale; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; CA, Cronbach's alpha; CDSS, Calgary Depression Scale for Schizophrenia; FEP, first-episode psychosis; HARS, Hamilton Anxiety rating Scale; ICC: inter-rater correlation coefficient; KC, kappa coefficient; MDD, major depressive disorder; TMS, transcranial magnetic stimulation; YMRS, Young Mania Rating Scale. Data values are mean 7 standard deviation unless otherwise stated.

recently-diagnosed patients with schizophrenia, avolition was considered to be present in 60% of cases (Perkins et al., 2000). The Montgomery–Asberg Depression Rating Scale (MADRS) is widely used in clinical trials to measure the effects of drug treatment in patients with MDD (Montgomery and Asberg, 1979). A single item, ‘lassitude’, has been utilised as a proxy for apathy, and a number of clinical trials have demonstrated the sensitivity of this item to the effects of antidepressant drug (Soares et al., 2009; Robinson et al., 2007; Wade and Friis Andersen, 2006; Raskin et al., 2012). The Hamilton Depression Rating Scale (HDRS) is another widely-used tool in antidepressant clinical trials (Hamilton, 1960). A single item ‘work and loss of interest’ encompasses difficulties at work and decreased productivity (Soares et al., 2009). The Social Adaptation Self-evaluation Scale (SASS) was developed specifically for use in clinical trials to evaluate effects of antidepressant drugs, with the aim of assessing social motivation from the patient's perspective (Bosc et al., 1997). The SASS has been validated in both the general population and in controlled studies evaluating reboxetine in MDD patients. It was found to demonstrate high internal validity, good test–retest reliability and sensitivity to change (Bosc, 2000). However, the SASS is not widely used. Mood and fatigue are explored by the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) (Fava et al., 2009). In patients with MDD, MGH-CPFQ demonstrated strong internal consistency, and was sensitive to change. However, scores for the two motivation items have not been reported. A recently-designed self-rated tool contains items that are scored according to how positive respondents feel (Nierenberg et al., 2012). The Clinical Positive Affect Scale (CPAS) has been used in one clinical study to date (in patients with bipolar disorder), where it demonstrated sensitivity to change with treatment, although this was a summary score rather than individual item scores (Deckersbach et al., 2012).

5.

Recommendations

Apathy should ideally be evaluated using the clinician's objective assessment, together with reports from the caregiver and patient, in order to gain a complete picture of the patient's neuropsychological status.

The AES was designed specifically to assess apathy in detail. It has been validated in patients across numerous neuropsychiatric conditions and may be used to define populations for clinical trials. However, the thresholds defined for clinically significant apathy vary across studies. This scale has demonstrated sensitivity to treatment effects in a small number of studies. Factor analysis has produced an AES-apathy domain, which may allow an even more specific focus on the core aspects of apathy, although this has not been applied in many studies to date. Of the other apathy-specific scales, only the AS and LARS seem to be used in clinical trials. The NPI is not a specific apathy assessment tool, but NPIapathy subscale score has been found to be highly reliable across numerous clinical studies in patients with AD, PD and other conditions. In addition, unlike the AES, there is a generally accepted NPI-apathy score threshold value for the identification of clinically significant apathy. This has therefore been used as a screening measure for inclusion of patients in clinical trials. In addition, it has been shown to be sensitive to treatment effects in numerous studies. Other rating scales designed for use in individuals with neuropsychiatric disorders may contain subscales or single items relating to apathy. Their specific use in clinical trials has not been widely reported, with the possible exception of the SANS-avolition-apathy subscale, and change over time or in response to treatment is therefore largely unknown. Furthermore, these tools (and their ‘apathy’ or ‘avolition’ subdomains) often contain items unrelated to apathy, which precludes their utility in clinical trials. At present, the AES and the NPI both seem to offer utility for the screening of apathy, while the NPI is a more established tool for determining changes in response to interventions in the clinical trial setting.

6. Limitations and requirements for future research A key issue for the validity of any apathy assessment tools is the absence of universally-accepted diagnostic criteria. A set of such criteria has been devised but there are issues regarding the validity of these (Robert et al., 2009; Clarke et al., 2011; Starkstein, 2012). This makes it difficult to validate assessment scales; position results obtained using


18 rating scales containing components measuring apathy into a clinically meaningful context; explore the impact of apathy on the illness as a whole; and judge or compare the effects of treatment interventions across studies. The currently available rating scales that measure apathy are often cross-validated against each other rather than against an agreed construct of apathy, which is largely meaningless. The absence of a precisely-defined construct of apathy also increases the likelihood of bias within any scale used to measure it. In order to assess the epidemiology of apathy, large studies are needed in the general population to ascertain its distribution. This would enable the determination of appropriate threshold values for defining the presence of clinical apathy. These could then be used to validate the currently available assessment tools to evaluate their utility in clinical trials and in clinical practice, or to inform the development of new assessment tools. However, a single universal measure of apathy across different neuropsychiatric disorders may not be appropriate or enable accurate detection in all patient groups (Clarke et al., 2011).

Role of the funding source Editorial assistance was funded by Roche.

Contributors Both the authors were involved in the preparation of all drafts of the manuscript and contributed to, and approved, the final manuscript.

Conflict of interest Dr. Weiser received no fee or honorarium for the writing or submission of this manuscript. He has no conflict of interest. Dr. Garibaldi is an employee of Hoffmann LaRoche.

Acknowledgements The author would like to thank Bridge Medical for their assistance with the preparation of this manuscript. Editorial assistance was funded by Roche.

References Ahearn, D.J., McDonald, K., Barraclough, M., Leroi, I., 2012. An exploration of apathy and impulsivity in Parkinson disease. Curr. Gerontol. Geriatr. Res. 2012, 390701. Alphs, L.D., Summerfelt, A., Lann, H., Muller, R.J., 1989. The negative symptom assessment: a new instrument to assess negative symptoms of schizophrenia. Psychopharmacol. Bull. 25, 159–163. Alphs, L., Morlock, R., Coon, C., van Willigenburg, A., Panagides, J., 2010. The 4-item negative symptoms assessment (NSA-4) instrument: a simple tool for evaluating negative symptoms in schizophrenia following brief training. Psychiatry (Edgemont) 7, 26–32. Alphs, L., Morlock, R., Coon, C., Cazorla, P., Szegedi, A., Panagides, J., 2011. Validation of a 4-item negative symptom assessment (NSA-4): a short-practical clinical tool for the assessment of

M. Weiser, G. Garibaldi negative symptoms in schizophrenia. Int. J. Methods Psychiatr. Res. 20, e31–e37. Alvarez, E., Ciudad, A., Olivares, J.M., Bousono, M., Gomez, J.C., 2006. A randomized, 1-year follow-up study of olanzapine and risperidone in the treatment of negative symptoms in outpatients with schizophrenia. J. Clin. Psychopharmacol. 26, 238–249. Andreasen, N.C., 1982. Negative symptoms in schizophrenia. Definition and reliability. Arch. Gen. Psychiatry 39, 784–788. Axelrod, B.N., Goldman, R.S., Woodard, J.L, Alphs, L.A., 1993. Validation of the 16-item negative symptom assessment. J. Psychiatr. Res. 27, 253–258. Benito-Leon, J., Cubo, E., Coronell, C., on behalf of the ANIMO Study Group, 2012. Impact of apathy on health-related quality of life in recently diagnosed Parkinson's disease: the ANIMO study. Mov. Disord. 27, 211–218. Biancosino, B., Picardi, A., Marmai, L., Biondi, M., Grasi, L., 2010. Factor structure of the brief psychiatric rating scale in unipolar depression. J. Affect. Disord. 124, 329–334. Bosc, M., Dubini, A., Polin, V., 1997. Development and validation of a social functioning scale, the social adaptation self-evaluation scale. Eur. Neuropsychopharmacol. 7 (1), S57–S70. Bosc, M., 2000. Assessment of social functioning in depression. Compr. Psychiatry 41, 63–69. Cannon-Spoor, H.E., Potkin, S.G., Wyatt, R.J., 1982. Measurement of premorbid adjustment in chronic schizophrenia. Schizophr. Bull. 8, 470–484. Chaudhuri, K.R., Martinez-Martin, P., Schapira, A.H., Stocchi, F., Sethi, K., Odin, P., Brown, R.G., Koller, W., Barone, P., MacPhee, G., Kelly, L., Rabey, M., MacMahon, D., Thomas, S., Ondo, W., Rye, D., Forbes, A., Tluk, S., Dhawan, V., Bowron, A., Williams, A.J., Olanow, C.J., 2006. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson's disease: the NMSQuest study. Mov. Disord. 21, 916–923. Chaudhuri, K.R., Martinez-Martin, P., Brown, R.G., Sethi, K., Stocchi, F., Odin, P., Ondo, W., Abe, K., MacPhee, G., MacMahon, D., Barone, P., Rabey, M., Forbes, A., Breen, K., Tluk, S., Naidu, Y., Olanow, C.J., Williams, A.J., Thomas, S., Rye, D., Tsuboi, Y., Hand, A., Schapira, A.H., 2007. The metric properties of a novel non-motor symptoms scale for Parkinson's disease: results from an international pilot study. Mov. Disord. 22, 1901–1911. Choi, J., Mogami, T., Medalia, A., 2009. Intrinsic Motivation Inventory: an adapted measure for schizophrenia research. Schizophr. Bull. 36, 966–976. Clarke, D.E., van Reekum, R., Simard, M., Streiner, D.L., Freedman, M., Conn, D., 2007. Apathy in dementia: an examination of the psychometric properties of the apathy evaluation scale. J. Neuropsychiatr. Clin. Neurosci. 19, 57–64. Clarke, D.E., van Reekum, R., Simard, M., Streiner, D.L., Conn, D., Cohen, T., Freedman, M., 2008. Apathy in dementia: clinical and sociodemographic correlates. J. Neuropsychiatry Clin. Neurosci. 20, 337–347. Clarke, D.E., Ko, J.Y., Kuhl, E.A., van Reekum, R., Salvador, R., Marin, R.S., 2011. Are the available apathy measures reliable and valid? A review of the psychometric evidence. J. Psychosom. Res. 70, 73–97. Cramer, C.K., Friedman, J.H., Amick, M.M., 2010. Olfaction and apathy in Parkinson's disease. Parkinsonism Relat. Disord. 16, 124–126. Cubo, E., Benito-León, J., Coronell, C., Armesto, D., on behalf of the ANIMO study group, 2012. Clinical correlates of apathy in patients recently diagnosed with Parkinson's disease: the ANIMO study. Neuroepidemiology 38, 48–55. Cuesta, M.J., García de Jalón, E., Campos, M.S., Ibáñez, B., Sánchez-Torres, A.M., Peralta, V., 2012. Duration of untreated negative and positive symptoms of psychosis and cognitive


Quantifying motivational deficits and apathy: A review of the literature impairment in first episode psychosis. Schizophr. Res. 141, 222–227. Cummings, J.L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D.A., Gornbein, J., 1994. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 44, 2308–2314. Cummings, J.L., 1997. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology 48 (Suppl. 6), S10–S16. Cummings, J.L., Nadel, A., Masterman, D., Cyrus, P.A., 2001. Efficacy of metrifonate in improving the psychiatric and behavioral disturbances of patients with Alzheimer's disease. J. Geriatr. Psychiatry Neurol. 14, 101–108. Cummings, J.L., 2009. last accessed 12.07.2013). Neuropsychiatric Inventory. Comprehensive assessment of psychopathology in patients with dementia Available at. de Medeiros, K., Robert, P., Gauthier, S., Stella, F., Politis, A., Leoutsakos, J., Taragano, F., Kremer, J., Brugnolo, A., Porsteinsson, A.P., Geda, Y.E., Brodaty, H., Gazdag, G., Cummings, J., Lyketsos, C., 2010. The neuropsychiatric inventory-clinician rating scale (NPI-C): reliability and validity of a revised assessment of neuropsychiatric symptoms in dementia. Int. Psychogeriatr. 22, 984–994. Deckersbach, T., Holzel, B.K., Eisner, L.R., Stange, J.P., Peckham, A.D., Dougherty, DD., Rauch, S.L., Lazar, S., Nierenberg, A.A., 2012. Mindfulness-based cognitive therapy for nonremitted patients with bipolar disorder. CNS Neurosci. Ther. 18, 133–141. Denheyer, M., Kiss, Z.H., Haffenden, A.S., 2009. Behavioral effects of subthalamic deep brain stimulation in Parkinson's disease. Neuropsychologia 47, 3203–3209. Drapier, D., Peron, J., Leray, E., Sauleau, P., Biseul, I., Drapier, S., Le Jeune, F., Travers, D., Bourguignon, A., Haegelen, C., Millet, B., Verin, M., 2008. Emotion recognition impairment and apathy after subthalamic nucleus stimulation in Parkinson's disease have separate neural substrates. Neuropsychologia 46, 2796–2801. Drijgers, R.L., Dujardin, K., Reijnders, J.S.A.M., Defebvre, L., Leentjens, A.F.G., 2010. Validation of diagnostic criteria for apathy in Parkinson's disease. Parkinsonism Relat. Disord. 16, 656–660. Drye, L.T., Scherer, R.W., Lanctôt, K.L., Rosenberg, P.B., Herrmann, N., Bachman, D., Mintzer, J.E., for the ADMET Research Group, 2013. Designing a trial to evaluate potential treatments for apathy in dementia: the apathy in dementia methylphenidate trial (ADMET). Am. J. Geriatr. Psychiatry 21, 549–559. Dujardin, K., Sockeel, P., Delliaux, M., Destee, A., Defebvre, L., 2008. The Lille apathy rating scale: validation of a caregiverbased version. Mov. Disord. 23, 845–849. Dujardin, K., Sockeel, P., Carette, A.S., Delliaux, M., Defebvre, L., 2013. Assessing apathy in everday clinical practice. Mov. Disord. 28, 2014–2019. Evensen, J., Røssberg, J.I., Barder, H., Haahr, U., ten Velden Hegelstad, W., Joa, I., Johannessen, J.O., Larsen, T.K., Melle, I., Opjordsmoen, S., Rund, B.R., Simonsen, E., Sundet, K., Vaglum, P., Friis, S., McGlashan, T., 2012. Apathy in first episode psychosis patients: a ten year longitudinal follow-up study. Schizophr. Res. 136, 19–24. Faerden, A., Nesvåg, R., Barrett, E.A., Agartz, I., Finset, A., Friis, S., Rossberg, J.I., Melle, I., 2008. Assessing apathy: the use of the apathy evaluation scale in first episode psychosis. Eur. Psychiatry 23, 33–39. Faerden, A., Friis, S., Agartz, I., Barrett, E.A., Nesvåg, R., Finset, A., Melle, I., 2009. Apathy and functioning in first-episode psychosis. Psychiatr. Serv. 60, 1495–1503. Fava, M., Iosifescu, D., Pedrelli, P., Baer, L., 2009. Reliability and validity of the Massachusetts general hospital cognitive and physical functioning questionnaire. Psychother. Psychosom. 78, 91–97.

19

Fehnel, S.E., Bann, C.M, Hogue, S.L., Kwong, W.J., Mahajan, S.S., 2004. The development and psychometric evaluation of the motivation and energy inventory. Qual. Life Res. 13, 1321–1336. Ferencz, B., Scholtissen, B., Bogorodskaya, M., Okun, M.S., Bowers, D., 2012. Toys and gadgets: construct validity of apathy in Parkinson's disease. J. Neuropsychiatry Clin. Neurosci. 24, 463–471. Ferrero-Arias, J., Gonzalez-Bernal, J., Lara-Ortega, F., da SilvaGonzalez, A., Diez-Lopez, M., 2011. The efficacy of nonpharmacological treatment for dementia-related apathy. Alzheimer Dis. Assoc. Disord. 25, 213–219. Frakey, L.L., Salloway, S., Buelow, M., Malloy, P., 2012. A randomized, double-blind, Placebo-controlled trial of modafinil for the treatment of apathy in individuals with mild-to-moderate Alzheimer's disease. J. Clin. Psychiatry 73, 796–801. Gallagher, D.A., Goetz, C.G., Stebbins, G., Lees, A.J., Schrag, A., 2012. Validation of the MDS-UPDRS Part I for nonmotor symptoms in Parkinson's disease. Mov. Disord. 27, 79–83. Gauthier, S., Feldman, H., Hecker, J., Vellas, B., Ames, D., Subbiah, P., Whalen, E., Emir, B., Donepezil MSAD Study Investigators Group, 2002. Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease. Int. Psychogeriatr. 14, 389–404. Grace, J., Malloy, P.F., 2001. Frontal Systems Behavior Scale (FrSBe): Professional Manual. Psychological Assessment Resources, Lutz, FL. Grant, P.M., Huh, G.A., Perivoliotis, D., Stolar, N.M., Beck, A.T., 2012. Randomized trial to evaluate the efficacy of cognitive therapy for low-functioning patients with schizophrenia. Arch. Gen. Psychiatry 69, 121–127. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56–62. Heinrichs, D.W., Hanlon, T.E., Carpenter Jr., W.T., 1984. The quality of life scale: an instrument for rating the schziophrenic deficit symdrome. Schizophr. Bull. 10, 388–398. Horan, W.P., Kring, A.M., Gur, R.E., Reise, S.P., Blanchard, J.J., 2011. Development and psychometric validation of the clinical assessment interview for negative symptoms (CAINS). Schizophr. Res. 132, 140–145. Hsieh, C.J., Chu, H., Cheng, J.J., Shen, W.W., Lin, C.C., 2012. Validation of apathy evaluation scale and assessment of severity of apathy in Alzheimer's disease. Psychiatry Clin. Neurosci. 66, 227–234. Kaufer, D.I., Cummings, J.L., Ketchel, P., Smith, V., MacMillan, A., Shelley, T., Lopez, O.L., DeKosky, S.T., 2000. Validation of the NPI-Q, a brief clinical form of the neuropsychiatric inventory. J. Neuropsychiatry Clin. Neurosci. 12, 233–239. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261–276. Kimhy, D., Yale, S., Goetz, R.R., Marcinko McFarr, L., Malaspina, D., 2006. The factorial structure of the schedule for the deficit syndrome in schizophrenia. Schizophr. Bull. 32, 274–278. Kirkpatrick, B., Buchanan, R.W., McKenney, P.D., Alphs, L.D., Carpenter Jr., W.T., 1989. The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res. 30, 119–123. Kirkpatrick, B., Strauss, G.P., Nguyen, L., Fischer, B.A., Daniel, D. G., Cienfuegos, A., Marder, S.R., 2011. The brief negative symptom scale: psychometric properties. Schizophr. Bull. 37, 300–305. Kirsch-Darrow, L., Marsiske, M., Okun, M.S., Bauer, R., Bowers, D., 2011. Apathy and depression: separate factors in Parkinson's disease. J. Int. Neuropsychol. Soc. 17, 1058–1066. Kitajima, R., Miyamoto, S., Tenjin, T., Ojima, K., Ogino, S., Miyake, N., Fujiwara, K., Funamoto, Y., Arai, J., Tsukahara, S., Ito, Y., Tadokoro, M., Anai, K., Kaneda, Y., Yamaguchi, N., 2012. Effects of tapering of long-term benzodiazepines on cognitive function


20 in patients with schizophrenia receiving a second-generation antipsychotic. Prog. Neuropsychopharmacol. Biol. Psychiatry 36, 300–306. Konstantakopoulos, G., Ploumpidis, D., Oulis, P., Patrikelis, P., Soumani, A., Papadimitriou, G.N., Politis, A.M., 2011. Apathy, cognitive deficits and functional impairment in schizophrenia. Schizophr. Res. 133, 193–198. Krauss, H., Marwinski, K., Held, T., Rietschel, M., Freyberger, H.J., 1998. Reliability and validity of the premorbid adjustment scale (PAS) in a German sample of schizophrenic and schizoaffective patients. Eur. Arch. Psychiatry Clin. Neurosci. 248, 277–281. Kring, A.M., Gur, R.E., Blanchard, J.J., Horan, W.P., Reise, S.P., 2013. The clinical assessment interview for negative symptoms (CAINS): final development and validation. Am. J. Psychiatry 170, 165–172. Kuhlmei, A., Walther, B., Becker, T., Muller, U., Nikolaus, T., 2013. Actigraphic daytime activity is reduced in patients with cognitive impairment and apathy. Eur. Psychiatry 28, 94–97. Lam, L.C., Lui, V.W., Luk, D.N., Chau, R., So, C., Poon, V., Tam, P., Ching, R., Lo, H., Chiu, J., Fung, A., Ko, F.S., 2012. Effectiveness of an individualized functional training program on affective disturbances and functional skills in mild and moderate dementia – a randomized controlled trial. Int. J. Geriat. Psychiatry 25, 133–141. Legault, L., Green-Demers, I., Pelletier, L., 2006. Why do high school students lack motivation in the classroom? Toward an understanding of academic amotivation and the role of social support. J. Educ. Psychol. 98, 567–582. Leontjevas, R., Evers-Stephan, A., Smalbrugge, M., Pot, A.M., Thewisson, V., Gerritsen, D.L., Koopmans, R.T.C.M., 2012. A comparative validation of the abbreviated apathy evaluation scale (AES-10) with the neuropsychiatric inventory apathy subscale against diagnostic criteria of apathy. J. Am. Med. Dir. Assoc. 308, e1–e6. Lenze, E.J., Skidmore, E.R., Begley, A.E., Newcomer, J.W., Butters, M.A., Whyte, E.M., 2012. Memantine for late-life depression and apathy after a disabling medical event: a 12-week, double-blind placebo-controlled pilot study. Int. J. Geriatr. Psychiatry 27, 974–980. Leroi, I., Ahearn, D.J., Andrew, M., McDonald, K.R., Byrne, E.J., Burns, A., 2011. Behavioural disorders, disability and quality of life in Parkinson's disease. Age. Ageing 40, 614–621. Lueken, U., Seidl, U., Völker, L., Schweiger, E., Kruse, A., Schröder, J., 2007. Development of a short version of the apathy evaluation scale specifically adapted for demented nursing home residents. Am. J. Geriatr. Psychiatry 15, 376–385. Lyne, J., O'Donoghue, B., Owens, E., Renwick, L., Madigan, K., Kinsella, A., Clarke, M., Turner, N., O'Callaghan, E., 2012. Prevalence of item level negative symptoms in first episode psychosis diagnoses. Schizophr. Res. 135, 128–133. Marangell, L.B., Johnson, C.R., Kertz, B., Zboyan, H.A., Martinez, J.M., 2002. Olanzapine in the treatment of apathy in previously depressed participants maintained with selective serotonin reuptake inhibitors: an open-label, flexible-dose study. J. Clin. Psychiatry 63, 391–395. Marin, R.S., Biedrzycki, R.C., Firinciogullari, S., 1991. Reliability and validity of the apathy evaluation scale. Psychiatr. Res. 38, 143–162. Marsh, L., Biglan, K., Gerstenhaber, M., Williams, J.R., 2009. Atomoxetine for the treatment of executive dysfunction in Parkinson's disease: an open-label study. Mov. Disord. 24, 277–282. Martinez-Martin, P., Rodriguez-Blazquez, C., Abe, K., Bhattacharyya, K.B., Bloem, B.R., Carod-Artal, F.J., Prakash, R., Esselink, R.A., Falup-Pecurariu, C., Gallardo, M., Mir, P., Naidu, Y., Nicoletti, A., Sethi, K., Tsuboi, Y., van Hilten, J.J., Visser, M., Zappia, M., Chaudhuri, K.R., 2009. International study on the

M. Weiser, G. Garibaldi psychometric attributes of the non-motor symptoms scale in Parkinson's disease. Neurology 73, 1584–1591. Mega, M.S., Masterman, D.M., O'Connor, S.M., Barclay, T.R., Cummings, J.L., 1999. The spectrum of behavioural responses to cholinesterase inhibitor therapy in Alzheimer disease. Arch. Neurol. 56, 1388–1393. Miyaoka, T., Wake, R., Furuya, M., Liaury, K., Ieda, M., Kawakami, K., Tsuchie, K., Taki, M., Ishihara, K., Araki, T., Horiguchi, J., 2012. Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study. Prog. Neuropsychopharmacol. Biol. Psychiatry 37, 222–226. Montgomery, S.A., Asberg, M., 1979. A new depression scale designed to be sensitive to change. Br. J. Psychiatry 134, 382–389. Morice, R., Urbanc, S., McNicol, D., 1985. The premorbid adjustment scale (PAS): its use in an Australian study. Aust. N. Z. J. Psychiatry 19, 390–395. Morley, J.F., Weintraub, D., Mamikonyan, E., Moberg, P.J., Siderowf, A.D., Duda, J.E., 2011. Olfactory dysfunction is associated with neuropsychiatric manifestations in Parkinson's disease. Mov. Disord. 26, 2051–2057. Mulin, E., Leone, E., Dujardin, K., Delliaux, M., Leentjens, A., Nobili, F., Dessi, B., Tible, O., Aguera-Ortiz, L., Osorio, R.S., Yessavage, J., Dachevsky, D., Verhey, F.R.J., Cruz Jentoft, A.J., Blanc, O., Llorca, P.M., Robert, P.H., 2011. Diagnostic criteria for apathy in clinical practice. Int. J. Geriatr. Psychiatry 26, 158–165. Nakaya, M., Ohmori, K., 2008. A two-factor structure for the schedule for the deficit syndrome in schizophrenia. Psychiatr. Res. 158, 256–259. Nazzaro, J.M., Pahwa, R., Lyons, K.E., 2011. The impact of subthalamic stimulation on non-motor symptoms of Parkinson's disease. Parkinsonism Relat. Disord. 17, 606–609. Nierenberg, A.A., Bentley, K.H., Farabaugh, A.H., Fava, M., Deckersbach, T., 2012. The absence of depressive symptoms is not the presence of wellness: validation of the clinical positive affect scale. Aust. NZ. J. Psychiatry 46, 1165–1172. Njomboro, P., Deb, S., 2012. Poor dissociation of patient-evaluated apathy and depressive symptoms. Curr. Gerontol. Geriatr. Res. 2012, 1–8. Norton, L.E., Malloy, P.E., Salloway, S., 2001. The impact of behavioral symptoms on activities of daily living in patients with dementia. Am. J. Geriatr. Psychiatry 9, 41–48. Onyike, C.U., Sheppard, J-M.E., Tschanz, J.T., Norton, M.C., Green, R.C., Steinberg, M., Welsh-Bohmer, K.A., Breitner, J.C., Lyketsos, C.G., 2007. Epidemiology of apathy in older adults: the cache county study. Am. J. Geriatr. Psychiatry 15, 365–375. Overall, J.E., Gorham, D.R., 1962. The brief psychiatric rating scale. Psychol. Rep. 10, 799–812. Padala, P.R., Burke, W.J., Shostrom, V.K., Bhatia, S.C., Wengel, S. P., Potter, J.F., Petty, F., 2010. Methylphenidate for apathy and functional status in dementia of the Alzheimer type. Am. J. Geriatr. Psychiatry 18, 371–374. Pedersen, K.F., Larsen, J.P., Aarsland, D., 2008. Validation of the unified Parkinson's disease rating scale (UPDRS) section I as a screening and diagnostic instrument for apathy in patients with Parkinson's disease. Parkinsonism Relat. Disord. 14, 183–186. Pelletier, L.G., Fortier, M.S., Vallerand, R.J., Tuson, K.M., Brière, N.M., Blais, M.R., 1995. Toward a new measure of intrinsic motivation, extrinsic motivation, and amotivation in sports: the sport motivation scale (SMS). J. Sport. Exercise Psychol. 17, 35–53. Perkins, D.O., Leserman, J., Jarskog, L.F., Graham, K., Kazmer, J., Lieberman, J.A., 2000. Characterizing and dating the onset of symptoms in psychotic illness: the symptom onset in schizophrenia (SOS) inventory. Schizophr. Res. 44, 1–10. Prikryl, R., Ustohal, L., Prikrylova Kucerova, H., Kasparek, T., Venclikova, S., Vrzalova, M., Ceskova, E., 2013. A detailed


Quantifying motivational deficits and apathy: A review of the literature analysis of the effect of repetitive transcranial magnetic stimulation on negative symptoms of schizophrenia: a doubleblind trial. Schizophr. Res. 149, 167–173. Raffard, S., Esposito, F., Boulenger, J-P., Van der Linden, M., 2013. Impaired ability to imagine future pleasant events is associated with apathy in schizophrenia. Psychiatr. Res 209, 393–400. Raskin, J., George, T., Granger, R.E., Hussain, N., Zhao, G.W., Marangell, L.B., 2012. Apathy in currently nondepressed patients treated with a SSRI for a major depressive episode: outcomes following randomized switch to either duloxetine or escitalopram. J. Psychiatr. Res. 46, 667–674. Ravindran, A.V., Kennedy, S.H., O'Donovan, M.C., Fallu, A., Camacho, F., Binder, C.E., 2008. Osmotic-release oral methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: results of a double-blind, randomized, placebo-controlled trial. J. Clin. Psychiatry 69, 87–94. Rios-Romenets, S., Wolfson, C., Galatas, C., Pelletier, A., Altman, R., Wadup, L., Postuma, R.B., 2012. Validation of the non-motor symptoms questionnaire (NMS-Quest). Parkinsonism Relat Disord. 18, 54–58. Robert, P.H., Clairet, S., Benoit, M., Koutaich, J., Bertogliati, C., Tible, O., Caci, H., Borg, M., Brocker, P., Bedoucha, P., 2002. The apathy inventory: assessment of apathy and awareness in Alzheimer's disease, Parkinson's disease and mild cognitive impairment. Int. J. Geriatr. Psychiatry 17, 1099–1105. Robert, P., Onyike, C.U., Leentjens, A.F.G., Dujardin, K., Aalten, P., Starkstein, S., Verhey, F.R.J., Yessavage, J., Clement, J.P., Drapier, D., Bayle, F., Benoit, M., Boyer, P., Lorca, P.M., Thibaut, F., Gauthier, S., Grossberg, G., Vellas, B., Byrne, J., 2009. Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders. Eur. Psychiatry 24, 98–104. Robinson, D.S., Gilmor, Y.L., Yang, Y., Moonsamy, G., Azzaro, A.J., Oren, D.A., Campbell, B.J., 2007. Treatment effects of selegiline transdermal system on symptoms of major depressive disorder: a meta-analysis of short-term, placebo-controlled, efficacy trials. Psychopharmacol. Bull. 40, 15–28. Rosenberg, P.B., Lanctot, K.L., Drye, L.T., 2013. Safety and efficacy of methylphenidate for apathy in Alzheimer's disease: a randomized, placebo-controlled trial. J. Clin. Psychiatry 74, 810–816. Rosenheck, R.A., Krystal, J.H., Lew, R., Barnett, P.G., Fiore, L., Valley, D., Thwin, S.S., Vertrees, J.E., Liang, M.H., for the CSP555 Research Group., 2011. Long-acting risperidone and oral antipsychotics in unstable schizophrenia. N. Engl. J. Med. 364, 842–851. Ryan, R.M., 1982. Control and information in the intrapersonal sphere: an extension of cognitive evaluation theory. J. Pers. Soc. Psychol. 43, 450–461. Shapiro, D.I., Marenco, S., Spoor, E.H., Egan, M.F., Weinberger, D. R., Gold, J.M., 2009. The premorbid adjustment scale as a measure of developmental compromise in patients with schizophrenia and their healthy siblings. Schizophr. Res. 112, 136–142. Soares, C.N., Kornstein, S.G., Thase, M.E., Jiang, Q., Guico-Pabia, C.J., 2009. Assessing the efficacy of desvenlafaxine for improving functioning and well-being outcome measures in patients with major depressive disorder: a pooled analysis of 9 doubleblind, placebo-controlled, 8-week clinical trials. J. Clin. Psychiatry 70, 1365–1371. Sockeel, P., Dujardin, K., Devos, D., Deneve, C., Destee, A., Defebvre, L., 2006. The Lille apathy rating scale (LARS), a new instrument for detecting and quantifying apathy: validation in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 77, 579–584. Starkstein, S.E., Mayberg, H.S., Preziosi, T.J., Andrezejewski, P., Leiguarda, R., Robinson, R.G., 1992. Reliability, validity, and clinical correlates of apathy in Parkinson's disease. J. Neuropsychiatry Clin. Neurosci. 4, 134–139.

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Starkstein, S.E., Fedoroff, J.P., Price, T.R., Leiguarda, R., Robinson, R.G., 1993. Apathy following cerebrovascular lesions. Stroke 24, 1625–1631. Starkstein, SE., Petracca, G., Chemerinski, E., Kremer, J., 2001. Syndromic validity of apathy in Alzheimer's disease. Am. J. Psychiatry 158, 872–877. Starkstein, S.E., Ingram, L., Garau, M.L., Mizrahi, R., 2005. On the overlap between apathy and depression in dementia. J. Neurol. Neurosurg. Psychiatry 76, 1070–1074. Starkstein, S.E., 2012. Apathy in Parkinson's disease: diagnostic and etiological dilemmas. Mov. Disord 27, 174–178. Stauffer, V.L., Song, G., Kinon, B.J., Ascher-Svanum, H., Chen, L., Feldman, P.D., Conley, R.R., 2012. Responses to antipsychotic therapy among patients with schizophrenia or schizoaffective disorder and either predominant or prominent negative symptoms. Schizophr. Res. 134, 195–201. Stout, J.C., Ready, R.E., Grace, J., Malloy, P.F., Paulsen, J.F., 2003. Factor analysis of the frontal systems behavior scale (FrSBe). Assessment 10, 79–85. Strauss, M.E., Sperry, S.D., 2002. An informant-based assessment of apathy in Alzheimer disease. Neuropsychiatry Neuropsychol. Behav. Neurol. 15, 176–183. Strauss, G.P., Keller, W.R., Buchanan, R.W., Gold, J.M., Fischer, B. A., McMahon, R.P., Catalano, L.T., Culbreth, A.J., Carpenter, W. T., Kirkpatrick, B., 2012. Next-generation negative symptom assessment for clinical trials: validation of the brief negative symptom scale. Schizophr. Res. 142, 88–92. Tas, C., Brown, E.C., Esen-Danaci, A., Lysaker, P.H., Brüne, M., 2012. Intrinsic motivation and metacognition as predictors of learning potential in patients with remitted schizophrenia. J. Psychiatr. Res. 46, 1086–1092. Thobois, S., Lhommee, E., Klinger, H., Ardouin, C., Schmitt, E., Bichon, A., Kistner, A., Castrioto, A., Xie, J., Fraix, V., Pelissier, P., Charbardes, S., Mertens, P., Quesada, J.L., Bosson, J.L., Pollak, P., Broussolle, E., Krack, P., 2013. Parkinsonian apathy responds to dopaminergic D2/D3 stimulation with piribedil. Brain 136, 1568–1577. Tran, P., Skolnick, P., Czobor, P., Huang, N.Y., Bradshaw, M., McKinney, A., Fava, M., 2012. Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: a randomized, doubleblind, placebo-controlled trial. J. Affect. Disord. 46, 64–71. van Mastrigt, S., Addington, J., 2002. Assessment of premorbid function in first-episode schizophrenia: modifications to the premorbid adjustment scale. J. Psychiatry Neurosci. 27, 92–101. Vallerand, R.J., Pelletier, L.G., Blais, M.R., Briere, N.M., Senecal, C., Vallieres, E.F., 1992. The academic motivation scale: a measure of intrinsic, extrinsic, and amotivation in education. Educ. Psychol. Meas. 52, 1003–1017. Varanese, S., Perfetti, B., Ghilardi, M.F., Di Rocco, A., 2011. Apathy, but not depression, reflects inefficient cognitive strategies in Parkinson's disease. PLoS One 6, e17846. Velligan, D.I., Ritch, J.L., Sui, D., DiCocco, M., Huntzinger, C.D., 2002. Frontal systems behavior scale in schizophrenia: relationships with psychiatric symptomatology, cognition, and adaptive function. Psychiatr. Res 113, 227–236. Ventura, J., Lukoff, D., Nuechterlein, K.H., Liberman, R.P., Green, M.F., Shaner, A., 1993. Training and quality assurance with the brief psychiatric rating scale. Int. J. Methods Psychiatr. Res 3, 221–244. Ventura, J., Nuechterlein, K.H., Subotnik, K.L., Gutkind, D., Gilbert, E.A., 2000. Symptom dimensions in recent-onset schizophrenia and mania: a principal components analysis of the 24item brief psychiatric rating scale. Psychiatr. Res 97, 129–135. Vialta-Franch, J., Calvo-Perxas, L., Garre-Olmo, J., Turro-Garriga, O, Lopez-Pousa, S., 2013. Apathy syndrome in Alzheimer's disease: prevalence, incidence, persistence, and risk and mortality factors. J. Alzheimer Disord 33, 535–543.


22 Wade, A., Friis Andersen, H., 2006. The onset of effect for escitalopram and its relevance for the clinical management of depression. Curr. Med. Res. Opin. 22, 2101–2110. Waldemar, G., Gauthier, S., Jones, R., Wilkinson, D., Cummings, J., Lopez, O., Zhang, R., Xu, Y., Sun, Y., Knox, S., Richardson, S., Mackell, J., 2011. Effect of donepezil on emergence of apathy in mild to moderate Alzheimer's disease. Int. J. Geriatr. Psychiatry 26, 150–157. Wilkinson, G., Hesdon, B., Wild, D., Cookson, R., Farina, C., Sharma, V., Fitzpatrick, R., Jenkinson, C., 2000. Self-report quality of life measure for people with schizophrenia: the SQLS. Br. J. Psychiatry. 177, 42–46. Wood, S., Cummings, J.L., Hsu, M.A., Barclay, T., Wheatley, M.E., Yarema, K.T., Schnelle, J.F., 2000. The use of the neuropsychiatric inventory in nursing home residents. Characterization and measurement. Am. J. Geriatr. Psychiatry 8, 75–83.

M. Weiser, G. Garibaldi Zanello, A., Berthoud, L., Ventura, J., Merlo, M.C.G., 2013. The brief psychiatric rating scale (version 4.0) factorial structure and its sensitivity in the treatment of outpatients with unipolar depression. Psychiatr. Res 210, 626–633. Ziropadja, J.J., Stefanova, E., Petrovic, M., Stojkovic, T., Kostic, V. S., 2012. Apathy and depression in Parkinson's disease: the Belgrade PD study report. Parkinsonism Relat. Disord. 18, 339–342. Zoccali, R., Muscatello, M.R., Cedro, C., Neri, P., La Torre, D., Spina, E., Di Rosa, A.E., Meduri, M., 2004. The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebocontrolled study. Int. Clin. Psychopharmacol. 19, 71–76.


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