- Email: [email protected]
Mood disorders in Parkinson's disease
Parkinsonism and Related Disorders 18S1 (2012) S74–S76
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Mood disorders in Parkinson’s disease Louis C.S. Tan* Department of Neurology, Parkinson’s Disease and Movement Disorders Centre, National Neuroscience Institute, Singapore, USA National Parkinson Foundation Centre of Excellence
article info
summary
Keywords: Depression Apathy Anxiety Neuropsychiatry Dementia Behaviour
An increasing emphasis has been placed on the identification and management of non-motor features of Parkinson’s disease (PD). Of the behavioural disorders in PD, mood disorders are amongst the most common and can occur in both early and late stages of PD. In some cases, these problems may even precede the development of motor symptoms of PD. These disorders have a major impact in the quality of life and affect daily function. This review will focus on depression, anxiety and apathy, and will discuss the epidemiological, clinical features, diagnosis and management of these disorders. The diagnosis and evaluation of these problems remain a challenge in view of the overlapping symptoms between these disorders and also with the clinical features of PD. The development and validation of diagnostic criteria and rating scales for these disorders remain a priority particularly in relation to anxiety and apathy. Another gap in the management of these disorders is the limited empirical evidence for the treatment of these problems. There is therefore an urgent need for systematic studies in the pharmacological and nonpharmacological management of these disorders to enable a holistic and evidence-based approach to the management of mood disorders in PD. © 2011 Elsevier Ltd. All rights reserved.
1. Introduction Mood disorder is the term designating a group of diagnoses in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV TR) classification system in which a disturbance in the person’s mood is the underlying feature. The most common mood disorders in Parkinson’s disease (PD) are depression, anxiety and apathy. These problems are common in PD and affect the majority of patients at some point in their disease. 2. Depression in PD Depression has been strongly associated with PD with previous studies estimating the prevalence rate to be between 2.7 to 90%. A recent systematic review found the weighted prevalence of major depressive disorder to be 17% of PD patients, that of minor depression to be 22% and dysthymia 13%. Clinically significant depressive symptoms were present in 35% of patients [1]. A few prospective studies have suggested that depression independently increased the risk of development of subsequent PD [2]. Depression is a key determinant of a reduced quality of life in PD [3]. It has also been associated with sleep disturbances, fatigue, decreased functional ability and impairment of activities of daily living. Other associations with depression such as current age, * Corresponding author. Dr Louis CS Tan. Department of Neurology, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore. Tel.: +65 6357 7171; fax: +65 6357 7137. E-mail address: [email protected] (L.C.S. Tan). 1353-8020/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.
gender, age of PD onset, decreased cognition, history of depression, disease duration and motor severity have been reported in some studies but not by others [4]. The cause of depression in PD (dPD) remains unknown. Two primary and not mutually exclusive hypotheses exist. The first argues that dPD represents a reactive state, resulting from the perception of progressive and social disabilities associated with the disorder. The other suggests that the cause of depression is intrinsic to PD itself, accounting for the occurrence of dPD patients prior to or at the onset of motor symptoms. In both instances, the induced neurochemical alterations are complex and probably include dopaminergic, serotonergic, and noradrenergic mechanisms. These findings have been supported by post-mortem studies, cerebrospinal fluid examinations and functional imaging [2]. The diagnosis of dPD can be confounded by an overlap of the motor features of PD and the clinical features of depression. Masked facies, bradyphrenia, fatigue, insomnia, and weight loss may inaccurately suggest depression in euthymic patients. Recognition by patients of their social isolation and dependency may reflect an accurate assessment of parkinsonian disability and not necessarily be associated with actual depressive feelings. The diagnosis of dPD therefore remains a challenge. The diagnostic criteria for dPD were reviewed by workgroup established by the National Institute for Neurological Disease and Stroke and the National Institute of Mental Health in 2006 [5]. The workgroup recommended that when using the DSM criteria to diagnose depression, an inclusive approach to symptom assessment be adopted to enhance reliability of ratings in PD and to avoid the
L.C.S. Tan / Parkinsonism and Related Disorders 18S1 (2012) S74–S76
need to attribute symptoms to a particular cause. In addition the workgroup recommended: a. the inclusion of subsyndromal depression in clinical research studies of depression of PD; b. the specification of timing of assessments for PD patients with motor fluctuations; and c. the use of informants for cognitively impaired patients. The proposed diagnostic criteria are provisional and require further validation [5]. A number of scales have been used to screen or measure the severity of depression. For screening purposes, the Montgomery and Asberg depression rating scale (MADRS), Hamilton depression scale (HAM-D), Beck depression inventory (BDI), Hospital Anxiety and Depression Scale, and geriatric depression scale have been shown to be valid. For measurements of severity of depressive symptoms, the MADRS, HAM-D, BDI, and Zung self-rating depression scales are useful instruments [2]. In the management of PD patients with depression, it is important to determine if the episodes of depression are associated with off-medication periods. If this is the case, anti-parkinsonian medications should be optimized to minimize or eliminate off-periods. If depressive episodes are not related to motor fluctuations, then the severity of symptoms should be determined to assess the need for treatment. In cases of mild depression, non-pharmacological management such as patient education, counseling, referral to patient support groups, and cognitivebehavioural therapy should be explored. The first randomized, controlled trial on cognitive-behavioural therapy (CBT) was recently reported. This trial compared CBT to clinical monitoring and found CBT to be associated with significant improvements in all clinicianrated and self-reported measures of depression. The CBT group also reported greater improvements in quality of life, coping and anxiety as well as less motor decline [6]. Despite the magnitude and impact of dPD, there is a shortage of properly conducted large, randomized, clinical trials of antidepressants in PD. The studies reported are limited by sample size, use of different scales, and heterogeneous patient populations. The main groups of drugs that have been evaluated are dopamine agonists, tricylic antidepressants (TCAs), and selective serotonergicand norepinehrine reuptake inhibitors (SSRIs and SNRIs). Amongst the dopamine agonists, pramipexole has been the most studied drug for its anti-depressant effects in PD. Previous openlabeled and retrospective analysis of randomized controlled studies had suggested beneficial effects of pramipexole on depression. A recent radomized, double-blind, placebo-controlled trial assessing the use of pramipexole for the treatment of depressive symptoms in PD found that pramipexole was significantly superior to placebo in reducing depressive symptoms in PD, with the direct effect of pramipexole on depressive symptoms accounting for 80% of the total treatment effect [7]. There have been at least 7 randomized controlled studies evaluating the efficacy of TCAs in dPD. Unfortunately, many of these were small studies with methodological problems. A double-blind, randomized, placebo-controlled study comparing desipramine (a TCA that predominantly inhibits noradrenergic reuptake) and citalopram (a SSRI) in 48 non-demented PD patients suffering major depression reported that desipramine induced a more intense short term effect on dPD than did citalopram after 14 days. Both antidepressants produced significant improvements in the MADRS scores after 30 days. However, citalopram’s acceptability was twice as high as that of desipramine [8]. A more recent randomized controlled trial on 52 dPD patients compared nortriptyline to the SSRI paroxetine CR and placebo. This study reported that nortriptyline was more effective than placebo in improving depressive symptoms, but there was no significant benefit in the paroxetine CR group compared to the placebo group [9].
S75
A recent systematic review and meta-analysis of randomized controlled trials in the treatment of dPD analyzed 10 studies. In comparison between SSRIs and placebo (6 studies), the combined risk was 1.08 (95% CI: 0.77–1.55, p = 0.67). In the comparison between SSRIs and TCAs (3 studies), the combined risk was 0.75 (95% CI: 0.39–1.41, p = 0.37). An acceptability analysis showed that SSRIs were generally well tolerated. The review concluded that there was insufficient evidence that SSRIs are effective in the treatment of dPD. However, due to the limited number of studies and the small sample sizes, a type II error (false negative) could not be excluded [10]. Other treatment options that have been explored in small studies and warrant further evaluation include treatment with omega-3 fatty acid supplements, bright light therapy, deep brain stimulation of the subthalamic nucleus, repetitive transcranial magnetic stimulation, and electroconvulsive therapy [2]. 3. Anxiety in PD The spectrum of anxiety disorders in PD includes panic attacks, generalized anxiety disorders, social phobias, phobic disorders, agoraphobia, obsessive-compulsive disorder, and anxiety disorders not otherwise specified. There are fewer studies on anxiety compared with dPD. Anxiety disorders, both episodic and generalized anxiety syndromes are more prevalent in patients with PD compared with normal and disease controls with prevalence rates estimated to range from 5.3% to 40% [11]. Amongst depressed PD patients 67% have been found to have a co-existing anxiety diagnosis [12]. Prospective cohort studies have found anxiety to be a risk factor for PD even after excluding cases of PD diagnosed within 2 years of administration of the anxiety scale [13]. A recent study found the current and lifetime prevalence of at least one anxiety disorder to be 43% and 49% respectively amongst a community physician based PD population. The most common diagnosis was anxiety disorder not otherwise specified (NOS), with a lifetime prevalence of 30%. NOS category is used for “disorders with prominent anxiety or phobic avoidance that do not meet criteria for any specific anxiety disorder”. Specific phobia (19%), panic disorders (10%), and social phobia (9%) were the next most prevalent anxiety disorders in this study. Compared with non-anxious subjects, panic disorder was significantly associated with earlier age of PD onset, motor fluctuations, and morning dystonia [14]. Anxiety associated with motor fluctuations has also been found to be associated with poorer health status in PD patients after accounting for co-morbid depression and other clinical features [15]. Anxiety in PD patients could involve a dopaminergic deficit directly or be due to interactions between dopaminergic deficits and deficits in noradrenergic and serotoninergic systems. From the pathophysiological standpoint, the association of anxiety and panic disorders with locus coeruleus and noradrenergic dysfunction in PD is consistent with Braak’s theory that the earliest pathological process in PD involves non-dopaminergic systems in the lower brainstem. Whether subjects with PD having panic disorder represent a subgroup with disproportionate involvement of the locus coeruleus and noradrenergic system is unclear. The use and clinical validity of the DSM anxiety criteria have not undergone the same systematic analysis and critique as dPD but suffer the same conceptual difficulties and problems with symptomatic overlap. It has been recommended that social phobia should not be diagnosed if the fear is only about being embarrassed by PD symptoms in public. A variety of rating scales have been used to evaluate anxiety with no specific one being consistently used or recommended in PD [2]. There is no trial evidence as to the treatment of anxiety in patients with PD. As a wide spectrum of anxiety symptoms from
S76
L.C.S. Tan / Parkinsonism and Related Disorders 18S1 (2012) S74–S76
insomnia and jitteriness to panic disorders may be induced by dopaminergic therapy, dose reduction or substitution of a different medication may be the best approach. In patients who experience anxiety or panic attacks during off periods, therapy should be directed at reducing off time by optimizing PD medications. The medications used to manage anxiety include benzodiazepines, low dose TCAs, buspirone, and SSRIs. SSRIs are currently favored for treatment of anxiety disorders as they have the least side-effects. Psychological interventions such as relaxation techniques, behavioural training, counseling, and massage therapy may also be considered. 4. Apathy in PD Apathy refers to a set of behavioural, emotional and cognitive features that involve reduced interest and motivation in goal directed behaviours, indifference and flattened affect. Some studies emphasis the lack of motivation whereas others focus on the lack of emotional responsiveness as the key feature. The diagnosis of apathy is challenging as it is commonly associated with related disorders such as depression, cognitive impairment, and fatigue. There are also overlapping diagnostic criteria and symptom rating scales between these disorders. The reported prevalence of apathy in PD is between 17 and 70%. Apathy has been associated with more severe cognitive impairment and a decreased ADL performance, and has been found to be a predictive factor for cognitive decline [16]. Independent risk factors for the development of apathy include dementia at baseline, a more rapid decline in speech, and axial impairment [17]. A recent study found that apathy increased linearly for patients undergoing unilateral DBS surgery to the STN or GPi pre-operatively to 6 months post-operatively [18]. The Diagnostic criteria for apathy have been proposed been validated in at least 2 studies. The criteria used in these 2 studies were similar and focused on diminished goal-directed behaviour, goal-directed cognition, and emotion as key diagnostic features [19,20]. In a critique of rating scales, only the Apathy scale was recommended to assess apathy in PD while the UPDRS item 4 was recommended for screening purposes [2]. Management of apathy includes patient and caregiver education to raise the awareness of this problem and treatment of associated disorders such as depression and dementia. Non-pharmacological strategies include providing an individual daily schedule and structure with varied activities to keep patients engaged and active. Possible pharmacological therapies include dopamine agonists, psychostimulants, modafanil, dopamine agonists, and testosterone although no proper clinical trials on apathy in PD patients have been conducted [2]. Conflict of interests The author has no conflicts of interest to declare.
References 1. Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leenjens AF. A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord 2008; 23(2):183–9. 2. Aarsland D, Marsh L, Schrag A. Neuropsychiatric symptoms in Parkinson’s disease. Mov Disord 2009;24:2175–86. 3. Schrag A. Quality of life and depression in Parkinson’s disease. J Neurol Sci 2006;248:151–7. 4. Holroyd S, Currie LJ, Wooten GF. Depression is associated with impairment of ADL, non motor function in Parkinson’s disease. Neurology 2005;64:2134–5. 5. Marsh L, McDonald WM, Cummings J, Ravina B, et al. Provisional diagnostic criteria for depression in Parkinson’s disease: report of an NINDS/NIMH work group. Mov Disord 2006;21:148–58. 6. Dobkin RD, Menza M, Allen LA, Gara MA, Mark MH, Tiu J, et al. Cognitivebehavioral therapy for depression in Parkinson’s disease: a randomized, controlled trial. Am J Psychiatry 2011;168:1066–74. 7. Barone P, Poewe W, Albrecht S, Debieuvre C, Massey D, Rascol O, et al. Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a randomized, double-blind, placebo-controlled trial. Lancet Neurol 2010;9:573–80. 8. Devos D, Dujardin K, Poirot I, Moreau C, Cottencin O, Thomas P, et al. Comparison of desipramine and citalopram treatments for depression in Parkinson’s disease: a double-blind, randomized, placebo-controlled study. Mov Disord 2008;23:850–7. 9. Menza M, Dobkin RD, Marin H, Mark MH, Gara M, Buyske S, et al. A controlled trial of antidepressants in patients with Parkinson’s disease and depression. Neurology 2009;72:886–92. 10. Skapinakis P, Bakola E, Salanti G, Lewis G, Kyritsis AP, Mavreas V. Efficacy and acceptability of selective serotonin reuptake inhibitors for the treatment of depression in Parkinson’s disease: a systematic review and meta-analysis of randomized controlled trials. BMC Neurology 2010, 10;49. 11. Walsh K, Bennett G. Parkinson’s disease and anxiety. Postgrad Med J 2001;77: 89–93. 12. Menza MA, Robertson-Hoffman DE, Bonapace AS. Parkinson’s disease and anxiety: comorbidity with depression. Biol Psychiatry 1993;34:465–70. 13. Weisskopf MG, Chen H, Schwarzschild MA, Kawachi I, Ascherio A. Prospective study of phobic anxiety and risk of Parkinson’s disease. Mov Disord 2003;18: 646–51. 14. Pontone GM, Williams JR, Anderson KE, Chase G, Goldstein SA, Grill S, et al. Prevalence of anxiety disorders and anxiety subtypes in patients with Parkinson’s disease. Mov Disord 2009;24:1333–8. 15. Pontone GM, Williams JR, Anderson KE, Chase G, Goldstein SR, Grill S, et al. Anxiety and self-perceived health status in Parkinson’s disease. Parkinsonism Relat Disord 2011;17:249–54. 16. Dujardin K, Sockeel P, Delliaux M, Destee A, Defebvre L. Apathy may herald cognitive decline and dementia in Parkinson’s disease. Mov Disord 2009;24: 2391–7. 17. Pederson KF, Alves G, Aarsland D, Larsen JP. Occurrence and risk factors for apathy in Parkinson’s disease: a 4-year prospective longitudinal study. J Neurol Neurosurg Psychiatry 2009;80:1279–82. 18. Kirsch-Darrow L, Zahodne LB, Marsiske, M, Okun MS, Foote KD, Bowers D. The trajectory of apathy after deep brain stimulation: from pre-surgery to 6 months post-surgery in Parkinson’s disease. Parkinsonism Relat Disord 2011;17(3):182–8. 19. Starkstein SE, Merello M, Jorge R, Brockman S, Bruce D, Power B. The syndromal validity and nosological position of apathy in Parkinson’s disease. Mov Disord 2009;24:1211–6. 20. Drijgers RL, Dujardin K, Reijnders JS, Defebvre L, Leentjens AF. Validation of diagnostic criteria for apathy in Parkinson’s disease. Parkinsonism Relat Disord 2010;16:656–60.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Mood disorders in Parkinson’s disease Louis C.S. Tan* Department of Neurology, Parkinson’s Disease and Movement Disorders Centre, National Neuroscience Institute, Singapore, USA National Parkinson Foundation Centre of Excellence
article info
summary
Keywords: Depression Apathy Anxiety Neuropsychiatry Dementia Behaviour
An increasing emphasis has been placed on the identification and management of non-motor features of Parkinson’s disease (PD). Of the behavioural disorders in PD, mood disorders are amongst the most common and can occur in both early and late stages of PD. In some cases, these problems may even precede the development of motor symptoms of PD. These disorders have a major impact in the quality of life and affect daily function. This review will focus on depression, anxiety and apathy, and will discuss the epidemiological, clinical features, diagnosis and management of these disorders. The diagnosis and evaluation of these problems remain a challenge in view of the overlapping symptoms between these disorders and also with the clinical features of PD. The development and validation of diagnostic criteria and rating scales for these disorders remain a priority particularly in relation to anxiety and apathy. Another gap in the management of these disorders is the limited empirical evidence for the treatment of these problems. There is therefore an urgent need for systematic studies in the pharmacological and nonpharmacological management of these disorders to enable a holistic and evidence-based approach to the management of mood disorders in PD. © 2011 Elsevier Ltd. All rights reserved.
1. Introduction Mood disorder is the term designating a group of diagnoses in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV TR) classification system in which a disturbance in the person’s mood is the underlying feature. The most common mood disorders in Parkinson’s disease (PD) are depression, anxiety and apathy. These problems are common in PD and affect the majority of patients at some point in their disease. 2. Depression in PD Depression has been strongly associated with PD with previous studies estimating the prevalence rate to be between 2.7 to 90%. A recent systematic review found the weighted prevalence of major depressive disorder to be 17% of PD patients, that of minor depression to be 22% and dysthymia 13%. Clinically significant depressive symptoms were present in 35% of patients [1]. A few prospective studies have suggested that depression independently increased the risk of development of subsequent PD [2]. Depression is a key determinant of a reduced quality of life in PD [3]. It has also been associated with sleep disturbances, fatigue, decreased functional ability and impairment of activities of daily living. Other associations with depression such as current age, * Corresponding author. Dr Louis CS Tan. Department of Neurology, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore. Tel.: +65 6357 7171; fax: +65 6357 7137. E-mail address: [email protected] (L.C.S. Tan). 1353-8020/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.
gender, age of PD onset, decreased cognition, history of depression, disease duration and motor severity have been reported in some studies but not by others [4]. The cause of depression in PD (dPD) remains unknown. Two primary and not mutually exclusive hypotheses exist. The first argues that dPD represents a reactive state, resulting from the perception of progressive and social disabilities associated with the disorder. The other suggests that the cause of depression is intrinsic to PD itself, accounting for the occurrence of dPD patients prior to or at the onset of motor symptoms. In both instances, the induced neurochemical alterations are complex and probably include dopaminergic, serotonergic, and noradrenergic mechanisms. These findings have been supported by post-mortem studies, cerebrospinal fluid examinations and functional imaging [2]. The diagnosis of dPD can be confounded by an overlap of the motor features of PD and the clinical features of depression. Masked facies, bradyphrenia, fatigue, insomnia, and weight loss may inaccurately suggest depression in euthymic patients. Recognition by patients of their social isolation and dependency may reflect an accurate assessment of parkinsonian disability and not necessarily be associated with actual depressive feelings. The diagnosis of dPD therefore remains a challenge. The diagnostic criteria for dPD were reviewed by workgroup established by the National Institute for Neurological Disease and Stroke and the National Institute of Mental Health in 2006 [5]. The workgroup recommended that when using the DSM criteria to diagnose depression, an inclusive approach to symptom assessment be adopted to enhance reliability of ratings in PD and to avoid the
L.C.S. Tan / Parkinsonism and Related Disorders 18S1 (2012) S74–S76
need to attribute symptoms to a particular cause. In addition the workgroup recommended: a. the inclusion of subsyndromal depression in clinical research studies of depression of PD; b. the specification of timing of assessments for PD patients with motor fluctuations; and c. the use of informants for cognitively impaired patients. The proposed diagnostic criteria are provisional and require further validation [5]. A number of scales have been used to screen or measure the severity of depression. For screening purposes, the Montgomery and Asberg depression rating scale (MADRS), Hamilton depression scale (HAM-D), Beck depression inventory (BDI), Hospital Anxiety and Depression Scale, and geriatric depression scale have been shown to be valid. For measurements of severity of depressive symptoms, the MADRS, HAM-D, BDI, and Zung self-rating depression scales are useful instruments [2]. In the management of PD patients with depression, it is important to determine if the episodes of depression are associated with off-medication periods. If this is the case, anti-parkinsonian medications should be optimized to minimize or eliminate off-periods. If depressive episodes are not related to motor fluctuations, then the severity of symptoms should be determined to assess the need for treatment. In cases of mild depression, non-pharmacological management such as patient education, counseling, referral to patient support groups, and cognitivebehavioural therapy should be explored. The first randomized, controlled trial on cognitive-behavioural therapy (CBT) was recently reported. This trial compared CBT to clinical monitoring and found CBT to be associated with significant improvements in all clinicianrated and self-reported measures of depression. The CBT group also reported greater improvements in quality of life, coping and anxiety as well as less motor decline [6]. Despite the magnitude and impact of dPD, there is a shortage of properly conducted large, randomized, clinical trials of antidepressants in PD. The studies reported are limited by sample size, use of different scales, and heterogeneous patient populations. The main groups of drugs that have been evaluated are dopamine agonists, tricylic antidepressants (TCAs), and selective serotonergicand norepinehrine reuptake inhibitors (SSRIs and SNRIs). Amongst the dopamine agonists, pramipexole has been the most studied drug for its anti-depressant effects in PD. Previous openlabeled and retrospective analysis of randomized controlled studies had suggested beneficial effects of pramipexole on depression. A recent radomized, double-blind, placebo-controlled trial assessing the use of pramipexole for the treatment of depressive symptoms in PD found that pramipexole was significantly superior to placebo in reducing depressive symptoms in PD, with the direct effect of pramipexole on depressive symptoms accounting for 80% of the total treatment effect [7]. There have been at least 7 randomized controlled studies evaluating the efficacy of TCAs in dPD. Unfortunately, many of these were small studies with methodological problems. A double-blind, randomized, placebo-controlled study comparing desipramine (a TCA that predominantly inhibits noradrenergic reuptake) and citalopram (a SSRI) in 48 non-demented PD patients suffering major depression reported that desipramine induced a more intense short term effect on dPD than did citalopram after 14 days. Both antidepressants produced significant improvements in the MADRS scores after 30 days. However, citalopram’s acceptability was twice as high as that of desipramine [8]. A more recent randomized controlled trial on 52 dPD patients compared nortriptyline to the SSRI paroxetine CR and placebo. This study reported that nortriptyline was more effective than placebo in improving depressive symptoms, but there was no significant benefit in the paroxetine CR group compared to the placebo group [9].
S75
A recent systematic review and meta-analysis of randomized controlled trials in the treatment of dPD analyzed 10 studies. In comparison between SSRIs and placebo (6 studies), the combined risk was 1.08 (95% CI: 0.77–1.55, p = 0.67). In the comparison between SSRIs and TCAs (3 studies), the combined risk was 0.75 (95% CI: 0.39–1.41, p = 0.37). An acceptability analysis showed that SSRIs were generally well tolerated. The review concluded that there was insufficient evidence that SSRIs are effective in the treatment of dPD. However, due to the limited number of studies and the small sample sizes, a type II error (false negative) could not be excluded [10]. Other treatment options that have been explored in small studies and warrant further evaluation include treatment with omega-3 fatty acid supplements, bright light therapy, deep brain stimulation of the subthalamic nucleus, repetitive transcranial magnetic stimulation, and electroconvulsive therapy [2]. 3. Anxiety in PD The spectrum of anxiety disorders in PD includes panic attacks, generalized anxiety disorders, social phobias, phobic disorders, agoraphobia, obsessive-compulsive disorder, and anxiety disorders not otherwise specified. There are fewer studies on anxiety compared with dPD. Anxiety disorders, both episodic and generalized anxiety syndromes are more prevalent in patients with PD compared with normal and disease controls with prevalence rates estimated to range from 5.3% to 40% [11]. Amongst depressed PD patients 67% have been found to have a co-existing anxiety diagnosis [12]. Prospective cohort studies have found anxiety to be a risk factor for PD even after excluding cases of PD diagnosed within 2 years of administration of the anxiety scale [13]. A recent study found the current and lifetime prevalence of at least one anxiety disorder to be 43% and 49% respectively amongst a community physician based PD population. The most common diagnosis was anxiety disorder not otherwise specified (NOS), with a lifetime prevalence of 30%. NOS category is used for “disorders with prominent anxiety or phobic avoidance that do not meet criteria for any specific anxiety disorder”. Specific phobia (19%), panic disorders (10%), and social phobia (9%) were the next most prevalent anxiety disorders in this study. Compared with non-anxious subjects, panic disorder was significantly associated with earlier age of PD onset, motor fluctuations, and morning dystonia [14]. Anxiety associated with motor fluctuations has also been found to be associated with poorer health status in PD patients after accounting for co-morbid depression and other clinical features [15]. Anxiety in PD patients could involve a dopaminergic deficit directly or be due to interactions between dopaminergic deficits and deficits in noradrenergic and serotoninergic systems. From the pathophysiological standpoint, the association of anxiety and panic disorders with locus coeruleus and noradrenergic dysfunction in PD is consistent with Braak’s theory that the earliest pathological process in PD involves non-dopaminergic systems in the lower brainstem. Whether subjects with PD having panic disorder represent a subgroup with disproportionate involvement of the locus coeruleus and noradrenergic system is unclear. The use and clinical validity of the DSM anxiety criteria have not undergone the same systematic analysis and critique as dPD but suffer the same conceptual difficulties and problems with symptomatic overlap. It has been recommended that social phobia should not be diagnosed if the fear is only about being embarrassed by PD symptoms in public. A variety of rating scales have been used to evaluate anxiety with no specific one being consistently used or recommended in PD [2]. There is no trial evidence as to the treatment of anxiety in patients with PD. As a wide spectrum of anxiety symptoms from
S76
L.C.S. Tan / Parkinsonism and Related Disorders 18S1 (2012) S74–S76
insomnia and jitteriness to panic disorders may be induced by dopaminergic therapy, dose reduction or substitution of a different medication may be the best approach. In patients who experience anxiety or panic attacks during off periods, therapy should be directed at reducing off time by optimizing PD medications. The medications used to manage anxiety include benzodiazepines, low dose TCAs, buspirone, and SSRIs. SSRIs are currently favored for treatment of anxiety disorders as they have the least side-effects. Psychological interventions such as relaxation techniques, behavioural training, counseling, and massage therapy may also be considered. 4. Apathy in PD Apathy refers to a set of behavioural, emotional and cognitive features that involve reduced interest and motivation in goal directed behaviours, indifference and flattened affect. Some studies emphasis the lack of motivation whereas others focus on the lack of emotional responsiveness as the key feature. The diagnosis of apathy is challenging as it is commonly associated with related disorders such as depression, cognitive impairment, and fatigue. There are also overlapping diagnostic criteria and symptom rating scales between these disorders. The reported prevalence of apathy in PD is between 17 and 70%. Apathy has been associated with more severe cognitive impairment and a decreased ADL performance, and has been found to be a predictive factor for cognitive decline [16]. Independent risk factors for the development of apathy include dementia at baseline, a more rapid decline in speech, and axial impairment [17]. A recent study found that apathy increased linearly for patients undergoing unilateral DBS surgery to the STN or GPi pre-operatively to 6 months post-operatively [18]. The Diagnostic criteria for apathy have been proposed been validated in at least 2 studies. The criteria used in these 2 studies were similar and focused on diminished goal-directed behaviour, goal-directed cognition, and emotion as key diagnostic features [19,20]. In a critique of rating scales, only the Apathy scale was recommended to assess apathy in PD while the UPDRS item 4 was recommended for screening purposes [2]. Management of apathy includes patient and caregiver education to raise the awareness of this problem and treatment of associated disorders such as depression and dementia. Non-pharmacological strategies include providing an individual daily schedule and structure with varied activities to keep patients engaged and active. Possible pharmacological therapies include dopamine agonists, psychostimulants, modafanil, dopamine agonists, and testosterone although no proper clinical trials on apathy in PD patients have been conducted [2]. Conflict of interests The author has no conflicts of interest to declare.
References 1. Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leenjens AF. A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord 2008; 23(2):183–9. 2. Aarsland D, Marsh L, Schrag A. Neuropsychiatric symptoms in Parkinson’s disease. Mov Disord 2009;24:2175–86. 3. Schrag A. Quality of life and depression in Parkinson’s disease. J Neurol Sci 2006;248:151–7. 4. Holroyd S, Currie LJ, Wooten GF. Depression is associated with impairment of ADL, non motor function in Parkinson’s disease. Neurology 2005;64:2134–5. 5. Marsh L, McDonald WM, Cummings J, Ravina B, et al. Provisional diagnostic criteria for depression in Parkinson’s disease: report of an NINDS/NIMH work group. Mov Disord 2006;21:148–58. 6. Dobkin RD, Menza M, Allen LA, Gara MA, Mark MH, Tiu J, et al. Cognitivebehavioral therapy for depression in Parkinson’s disease: a randomized, controlled trial. Am J Psychiatry 2011;168:1066–74. 7. Barone P, Poewe W, Albrecht S, Debieuvre C, Massey D, Rascol O, et al. Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a randomized, double-blind, placebo-controlled trial. Lancet Neurol 2010;9:573–80. 8. Devos D, Dujardin K, Poirot I, Moreau C, Cottencin O, Thomas P, et al. Comparison of desipramine and citalopram treatments for depression in Parkinson’s disease: a double-blind, randomized, placebo-controlled study. Mov Disord 2008;23:850–7. 9. Menza M, Dobkin RD, Marin H, Mark MH, Gara M, Buyske S, et al. A controlled trial of antidepressants in patients with Parkinson’s disease and depression. Neurology 2009;72:886–92. 10. Skapinakis P, Bakola E, Salanti G, Lewis G, Kyritsis AP, Mavreas V. Efficacy and acceptability of selective serotonin reuptake inhibitors for the treatment of depression in Parkinson’s disease: a systematic review and meta-analysis of randomized controlled trials. BMC Neurology 2010, 10;49. 11. Walsh K, Bennett G. Parkinson’s disease and anxiety. Postgrad Med J 2001;77: 89–93. 12. Menza MA, Robertson-Hoffman DE, Bonapace AS. Parkinson’s disease and anxiety: comorbidity with depression. Biol Psychiatry 1993;34:465–70. 13. Weisskopf MG, Chen H, Schwarzschild MA, Kawachi I, Ascherio A. Prospective study of phobic anxiety and risk of Parkinson’s disease. Mov Disord 2003;18: 646–51. 14. Pontone GM, Williams JR, Anderson KE, Chase G, Goldstein SA, Grill S, et al. Prevalence of anxiety disorders and anxiety subtypes in patients with Parkinson’s disease. Mov Disord 2009;24:1333–8. 15. Pontone GM, Williams JR, Anderson KE, Chase G, Goldstein SR, Grill S, et al. Anxiety and self-perceived health status in Parkinson’s disease. Parkinsonism Relat Disord 2011;17:249–54. 16. Dujardin K, Sockeel P, Delliaux M, Destee A, Defebvre L. Apathy may herald cognitive decline and dementia in Parkinson’s disease. Mov Disord 2009;24: 2391–7. 17. Pederson KF, Alves G, Aarsland D, Larsen JP. Occurrence and risk factors for apathy in Parkinson’s disease: a 4-year prospective longitudinal study. J Neurol Neurosurg Psychiatry 2009;80:1279–82. 18. Kirsch-Darrow L, Zahodne LB, Marsiske, M, Okun MS, Foote KD, Bowers D. The trajectory of apathy after deep brain stimulation: from pre-surgery to 6 months post-surgery in Parkinson’s disease. Parkinsonism Relat Disord 2011;17(3):182–8. 19. Starkstein SE, Merello M, Jorge R, Brockman S, Bruce D, Power B. The syndromal validity and nosological position of apathy in Parkinson’s disease. Mov Disord 2009;24:1211–6. 20. Drijgers RL, Dujardin K, Reijnders JS, Defebvre L, Leentjens AF. Validation of diagnostic criteria for apathy in Parkinson’s disease. Parkinsonism Relat Disord 2010;16:656–60.