Parkinson's Disease (Non-Motor and Non-Dopaminergic Features) || Anxiety Syndromes and Panic Attacks

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Chapter 18Anxiety Syndromes and Panic Attacks

Daniel Weintraub1,2,3,4 & Staci Hoops1

1Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA2Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA3Parkinson’s Disease Research, Education and Clinical Center (PADRECC), Veterans Affairs Medical Center, Philadelphia, PA, USA4Mental Illness Research, Education and Clinical Center (MIRECC), Veterans Affairs Medical Center, Philadelphia, PA, USA

Introduction

A wide range of anxiety disorders have been reportedto occur in Parkinson’s disease (PD), including general-ized anxiety disorder (GAD), panic attacks or disorders,social phobia, specific phobia, and, to a lesser degree,obsessive–compulsive disorder (OCD) [1,2].

Generalized anxiety disorder (GAD), as defined in theDiagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) [3], is characterized by excessive anxiety andworry about a number of activities and is associated withrestlessness, fatigue, difficulty in concentrating, irritabil-ity, muscle tension, or sleep disturbance.

A panic attack, which by itself is not a psychiatric dis-order, is characterized by a discrete period of intense fearor discomfort, in which a variety of symptoms developabruptly and reach a peak within 10 min. The symp-toms include palpitations, sweating, shaking, shortnessof breath, dizziness, depersonalization, and fear of dying.Panic disorder is recurrent, unexpected panic attacks pluspersistent concern about additional attacks, worry aboutthe implications or consequences of attacks, or a signifi-cant change in behavior related to the attacks.

Social phobia is characterized by a marked and persis-tent fear of one or more social situations. The individualfears that he or she will act in a way (or show anxietysymptoms) that will be embarrassing, but also recognizesthat the fear is excessive. DSM-IV-TR specifically statesthat individuals with social phobia may be vulnerable toa worsening of social anxiety and avoidance related to ageneral medical condition. However, if the social phobiasymptoms are limited to concerns about the general med-ical condition, then by convention a diagnosis of socialphobia is not made. Thus, if the patient only fears that hisor her PD symptoms will cause embarrassment in public,then criteria for social phobia are not met.

Obsessive–compulsive disorder (OCD) is characterized bycomplaints of persistent or repetitive thoughts (obses-

sions) or behaviors (compulsions). The person feels com-pelled to continue the thoughts or behaviors, despiteawareness that the thoughts or behaviors may be inap-propriate, and feels distress if he or she stops them. OCDmust be distinguished from both obsessive–compulsivepersonality disorder (OCPD) and impulse control disor-ders (ICDs). OCPD is a personality disorder characterizedby orderliness, perfectionism, and mental and interper-sonal control at the expense of flexibility, openness, andefficiency. ICDs are characterized by a failure to resist animpulse, drive, or temptation to perform a typically plea-surable activity that is ultimately harmful to the personor to others due to its excessive nature. ICDs that canoccur in PD include compulsive gambling, buying, sexualbehavior, and eating.

Specific phobia, formally known as simple phobia, is themost common of all anxiety disorders in the general pop-ulation. It is characterized by an excessive or unreason-able fear that is cued by the presence or anticipation of aspecific object or situation (e.g., flying, heights, animals,receiving an injection, seeing blood).

In addition to these formal psychiatric disorders, bothgeneral anxiety symptoms and discrete panic attacks havebeen reported to occur as part of “off” periods in PDpatients with motor fluctuations [4]. These symptoms aretypically classified as non-motor fluctuations (NMFs).

Epidemiology

GeneralIt has been reported in cross-sectional studies that upto 25–50% of PD patients experience some type of anxi-ety symptoms or disorders [1,2,5], and these prevalenceestimates far exceed those reported for anxiety disordersin the general population (5–15%) [1]. In addition, mostcomparison studies have found that anxiety disorders are

Parkinson’s Disease: Non-Motor and Non-Dopaminergic Features, First Edition. Edited by C. Warren Olanow, Fabrizio Stocchi, and Anthony E. Lang.c© 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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more common in PD than in other neurological disorders(e.g., multiple sclerosis) [6] or medical illnesses (e.g.,osteoarthritis) [5,7].

Specific anxiety disordersMost studies have reported that the most common anx-iety disorders in PD are panic disorder, phobic disorder,and GAD [5], and these disorders can be co-morbid [8].However, there has been limited research into the preva-lence of specific anxiety disorders in PD. One study of90 PD patients reported that 30% of the patients met cri-teria for panic disorder, 11.1% for GAD, and 3.3% forOCD [9]. Only panic disorder was more common in PDpatients than in an age- and sex-matched group, and co-morbid mood and anxiety disorders were more commonin PD patients than in controls (19.3% versus 8.6%, respec-tively). In another study of 131 PD patients, 24% of thepatients experienced recurrent panic attacks [10].

In a recent study that used a structured psychiatricinterview to examine the frequency of social phobiaand performance on the Liebowitz Social Anxiety Scale(LSAS) in PD [11], social phobia was diagnosed in 50% ofa convenience sample of 90 PD patients at a movementdisorder center. Approximately 80% of the patients whomet criteria of social phobia had generalized social phobia(i.e., fearful of or avoiding four or more social situations).

One study that administered an OCD inventory to PDpatients and normal controls found that PD patients withsevere disease had more OCD symptoms (i.e., check-ing, doubting, and cleaning subscales) than controls,whereas no difference was detected for patients withmilder disease [12]. Another study found that PD patientsscored higher than controls on an OCD ordering subscale,but had less OCD symptoms overall than patients withTourette’s syndrome or non-PD patients diagnosed withOCD [13]. In contrast, another study found that neitherOCD as a diagnosis nor OCD symptoms were more com-mon in PD than in matched controls [14].

In a small study, the lifetime prevalence of specific pho-bia in PD patients was reported to be 35.7%, significantlyhigher than the lifetime prevalence in the general popula-tion (8.9%) based on the results of a large epidemiologicalstudy [15]. Interestingly, 80% of the PD patients reportedto have a history of specific phobia had the onset of thesesymptoms prior to the onset of PD.

Non-motor fluctuationsNon-motor fluctuations (NMFs) have long been recog-nized as a feature of “off” periods in PD patients withmotor fluctuations; commonly reported NMFs includedepressive symptoms, anxiety symptoms, and slownessof thinking. In one of the few studies to study system-atically a range of NMF in patients with motor fluctu-ations, fluctuating anxiety symptoms were reported in66% of patients. Of this group, 88% reported experiencing

increased anxiety during “off” periods, 3% in the “pre-off” period, and 9% reported that anxiety and motor fluc-tuations occurred independently [4].

Deep brain stimulation (DBS)One recent review of neuropsychiatric complications ofDBS treatment found that anxiety was rarely discussedin studies of surgical treatments of PD [16]. Anotherreview of the neuropsychiatric complications of sub-thalamic nucleus (STN) DBS reported the occurrenceof transient confusion, emotional reactivity, depression,psychosis, and apathy post-surgery, but there was nomention of anxiety symptoms or disorders [17]. Theauthors made a point of noting that interpreting the lit-erature on the effects of DBS surgery on neuropsychi-atric symptoms is complicated by several factors, includ-ing patient selection bias, assessment measurement bias,and lack of systematic consideration of confounding vari-ables (e.g., changes in dopaminergic medications post-DBS surgery and psychosocial adjustment).

Impact of anxietyA recent study that assessed the impact of neuropsychi-atric symptoms on quality-of-life (QOL) using the Parkin-son’s Disease Questionnaire (PDQ-39) found that 77% ofPD patients had symptoms consistent with one or moreneuropsychiatric disorders [18]. Using the Hospital Anx-iety and Depression Scale (HADS) with a predeterminedcutoff point, 16.7% of patients reported clinically signif-icant anxiety symptoms. When analyses were controlledfor the severity of motor symptoms, increasing severityof anxiety (and also depression and hallucinations) wasassociated with poorer QOL.

In the aforementioned study of NMF, in which anxi-ety was the most commonly reported symptom, patientswere asked to rate the level of disability and incapac-ity caused by each subgroup (i.e., motor, dysautonomic,mental, or sensory subgroup) [4]. The level of disabilitycaused by psychic fluctuations correlated with the pres-ence of fluctuating anxiety, and 28% of patients reportedthat NMFs were more disabling than motor fluctuations.

In a cholinesterase inhibitor treatment study of patientswith PD with dementia (PDD), some patients were placedin a “mood” cluster based on elevated anxiety, depres-sion, and apathy scores. The caregivers of these patientswere found to have significantly higher caregiver distressscores [based on their Neuropsychiatric Inventory (NPI)scores] than the caregivers of patients without any neu-ropsychiatric co-morbidity [19].

Although there is little published research on the rel-ative impact of anxiety symptoms on QOL, function,or caregiver distress in PD, clinical experience indicatesthat many patients with co-morbid anxiety and depres-sion find the anxiety symptoms to be more distressingthan depressive symptoms, perhaps due to their intensity,



Anxiety Syndromes and Panic Attacks 195

accompanying somatic complaints, and propensity toworsen parkinsonism (i.e., increased tremor).

Correlates and risk factors

DemographicThere has been limited reporting on the demographic cor-relates of anxiety disorders in PD. One study of 90 PDpatients reported no association between the presence ofanxiety disorders and either age or sex [9].

Psychiatric and cognitiveThere is extensive overlap between anxiety and depres-sive symptoms or disorders in PD. Menza, Robertson-Hoffman, and Bonapace found that 92% of PD patientswith an anxiety disorder also met criteria for a depressivedisorder, and that 67% of those with a depressive disor-der also had an anxiety disorder [5]. Another study of PDpatients and age-matched spousal controls found that thecombination of depression and anxiety best differentiatedthe two populations [20].

As depression has been more extensively researchedand reported on in PD than in anxiety disorders, someexperts have suggested that anxiety in PD is secondary todepression, and that the extensive overlap makes depres-sion in PD distinct from idiopathic mood disorders [21].However, this prioritizing of depression over anxiety (i.e.,anxiety being a component of depression as opposedto being an independent disorder) is not based on anyempirical evidence, and is also not consistent with theclinical observation that many PD patients find anxi-ety symptoms to be more distressing and disabling thandepressive symptoms.

Definite conclusions about the relationship betweenanxiety and dementia in PD cannot be drawn due to lim-ited research and mixed results. Most studies either havefailed to comment on the cognitive status of their subjects,or demented patients were deliberately excluded. In onecholinesterase inhibitor treatment study of a large cohortof PDD patients, 49% of the patients were found to haveanxiety based on caregiver-rated scores using the NPI[19]. Using cluster analysis, 11% of patients were part ofa “mood” cluster, which included subjects with elevateddepression, anxiety, and apathy scores. Patients in themood cluster had higher MMSE scores than patients inthe “agitation” cluster and a trend for higher scores thanpatients in the “psychosis” cluster. In addition, femaleswere more likely to be in the mood cluster than in theunaffected group.

Excessive daytime sleepiness (EDS) has been shown tobe independently associated with anxiety in PD [22,23]. Inone study, anxiety was more strongly associated with EDSthan cognitive impairment, levodopa equivalent dailydosage (LEDD), and even depression. The authors spec-

ulated that loss of striatal and limbic dopaminergic trans-mission in PD results in reduced inhibitory control overthe amygdala, therefore leading to both anxiety and sleepdisturbances, with the latter resulting in EDS [22].

PD characteristicsAlthough research has been limited, no clear correlationhas been established between the presence of anxiety dis-orders and commonly examined clinical variables suchas laterality of motor signs, tremor- versus akinetic-rigid-predominant symptoms, severity of disease, age of PDonset, or PD duration [8,9].

The strongest association between anxiety and PD fea-tures is the high frequency of anxiety symptoms reportedas part of NMFs in patients with motor fluctuations.As previously mentioned, one study found that 66% ofpatients with motor fluctuations also reported anxiety asan NMF, with anxiety being the most common NMF [4].In the study, there was an association between occur-rence of NMFs and increasing severity of PD. In anotherstudy that assessed anxiety and parkinsonian disability[the latter using the self-rated Parkinson’s symptom diary(PSD)], anxiety scores were significantly higher during“off” periods (p < 0.03), and the magnitude of anxietycorrelated with changes in PSD scores (p = 0.006). Anxi-ety scores were also correlated with disease duration [24].In a study of panic attacks in PD by Vazquez, Jimenez-Jimenez, and Garcıa-Urra [10], a significant relationshipbetween panic attacks and both motor fluctuations anddyskinesias was reported. Additionally, patients withpanic attacks had an earlier age of PD onset, more severedisease as measured by Hoehn and Yahr staging, andgreater impairment in activities of daily living (ADLs).

In one of the few studies of OCD in PD, a significantcorrelation was found between both severity and dura-tion of illness and the Maudsley obsessional–compulsiveinventory (MOCI) total score. In this study, patients withmild PD did not report any obsessive–compulsive symp-toms [12].

The relationship between DBS and anxiety, and alsoother psychiatric and cognitive symptoms, is complex.One study of 15 consecutive PD patients assessed3 months before and both 3 and 6 months after DBS foundan overall increase in apathy, but no significant changein anxiety symptoms [25]. The authors speculated thatapathy and anxiety seemed to be incompatible, althoughthis has not been formally evaluated in PD. Anotherstudy of 72 consecutive PD patients found that 15 monthspost-STN DBS 12% of patients reported an increase and23% a decrease in severity of anxiety symptoms [26]. Inanother study that assessed a range of anxiety symptomsin the context of DBS, significant improvements over-all were reported in depression, anxiety, and psychoso-cial functioning [27]. However, on closer examination,23% reported improvement and 13% worsening on the



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State Anxiety Inventory (STAI), 19% reported improve-ment and 19% worsening on an obsessive–compulsivemeasure [from the Symptom-Checklist 90-R (SCL-90-R)], and 6% noted improvement and 10% worsening ofphobic anxiety (also from the SCL-90-R). The authorsconcluded that although STN stimulation can have a posi-tive impact on psychiatric symptoms, some patients expe-rience a worsening. It has also been noted that psychi-atric symptoms, including anxiety, can worsen even inpatients who experience a significant improvement inmotor symptoms with DBS [28]. Another study testedstable STN DBS patients “on” and “off” stimulation and“on” and “off” PD medications (2 × 2 study design), andfound no acute effect of either stimulation or medicationon anxiety scores [29].

Proposed risk factors for worsening of psychiatricsymptoms post-DBS include preoperative psychiatric dis-orders, direct surgical effects, stimulation effects, medica-tion changes, and psychosocial adjustment [28,30]. In astudy that assessed 40 consecutive PD patients presentingfor DBS, 78% were found to have at least one lifetime orcurrent psychiatric disorder, with a 40% prevalence rate ofanxiety disorders (GAD, panic attacks, or social phobia)[30]. The authors concluded that a range of psychiatricsymptoms are common in advanced PD patients who areexperiencing a diminishing response to, or complicationsof, dopamine replacement therapy.

Autonomic dysfunctionIn a study examining the association between autonomicsymptoms, anxiety, and depression in PD and matchedcontrol subjects, numerous autonomic symptoms (pos-tural dizziness, frequency of micturition, urinary hesi-tancy, constipation, dry mouth, impotence, and loss oflibido) were more common in PD patients than in controls[31]. Interestingly, anxiety and depression were associatedwith self-reported autonomic symptoms, but not withobjective measures of autonomic function. The authorssuggested that anxiety and depression in some PD sub-jects are likely to be a “behavioral phenocopy” causedby autonomic failure (i.e., symptom overlap leading tomisdiagnosis of anxiety and depressive disorders), andthat this may help explain the limited response to anti-depressant treatment in these patients [32].

Presentation

As mentioned previously, the four most commonlyreported anxiety disorders in PD are GAD, panic disor-der, social phobia, and OCD. No research suggests thatthe symptom profile for any of these disorders is differentthan that in the general population, as has been reportedfor depression [33].

When anxiety occurs as part of NMFs during “off”periods, patients may describe a sensation of feeling“trapped” as they become increasingly immobilized, withsymptoms resolving with improvement in motor symp-toms. However, motor and non-motor symptoms are notalways correlated [34].

In a study assessing the concurrent validity of threeanxiety inventories [the State–Trait Anxiety Inventory(STAI), the Hospital Anxiety Scale (HADS), and theHamilton Anxiety Scale (Ham-A), the main characteris-tics of anxiety were “inability to relax,” “restlessness orinability to feel calm,” and “feeling tense” [35].

Etiology and pathophysiology

Premorbid personality traits andpsychiatric disordersNumerous studies comparing PD patients and matchedcontrols have reported an increased prevalence of anxietyand depressive disorders in PD patients up to 20 yearsprior to PD onset [36,37]. In a recent systematic reviewof studies examining mental illness preceding PD onset,the authors reported on one case–control study and onecohort study examining pre-morbid anxiety and PD [38].The case–control study found a significant positive asso-ciation between a history of anxiety disorders and sub-sequent PD. The cohort study found a similar, althoughslightly less significant, association. The authors hypoth-esized that mid-life anxiety disorders involve neurobio-logical changes that increase susceptibility to the devel-opment of PD. This positive association between anxietydisorders in mid-life and subsequent development of PDsuggests a neurobiological underpinning to anxiety in PD.

A recent retrospective study reviewed 433 cases ofpathologically proven PD to ascertain presenting symp-toms [39]. One-fifth of patients presented with exclu-sively non-motor symptoms (NMS), and 12.1% of thosepatients had depression or anxiety. Within 2 years ofdisease onset, 24.7% had developed depression or anxi-ety symptoms. Not surprisingly, patients presenting withNMS were more likely to have a delay in their PDdiagnosis compared with patients presenting with motorsymptoms (median interval = 1.6 years versus 1.0 years,respectively). These findings underscore the fact that adiagnosis of PD needs to be considered in the differen-tial diagnosis of patients presenting with mid- or late-lifeanxiety symptoms.

There has also been widespread interest in the possi-bility of a “parkinsonian personality” that predates theonset of PD motor symptoms. In a recent review ofthis literature, the authors found only four studies thatattempted to assess pre-morbid personality in PD patients[40]. Three of four studies with a control group reportedpersonality differences between PD patients and controls,




and found PD patients to be more cautious, apprehensive,self-reproaching, and less novelty seeking. In anotherstudy of over 7000 adults in the general population whocompleted the Minnesota Multiphasic Personality Inven-tory (MMPI) in the 1960s, subjects who scored in the top25th percentile on “psychasthenia” (a measure of anxiety)were twice as likely (odds ratio = 1.95) to develop PD overthe next 40 years as those in the bottom 75th percentile[41]. The “traits” studied overlapped with the symptomsof generalized anxiety disorder, so this research raisesthe possibility that patients who go on to develop PDare more likely to have an anxious temperament. Futureresearch will need to determine if such traits are a risk fac-tor for PD, an early manifestation of PD, or linked to PDvia common risk factors or a common genetic predisposi-tion.

DopamineThere has been limited research on the associationbetween anxiety symptoms and the use of anti-parkinsonian medications in PD. In a small study exam-ining the correlates of anxiety disorders in PD patients,there were no differences between patients with and with-out an anxiety disorder in levodopa dosage or total lev-odopa exposure [8]. Another study of anxiety in PD foundno correlation between levodopa dosage and severity ofanxiety symptoms [5]. Yet another study reported thatanxiety symptoms in PD patients were as common priorto levodopa initiation as after starting levodopa treat-ment [20]. Regarding other PD medications, a small studyof levodopa-treated PD patients found no difference inanxiety symptoms based on the absence or presence ofadjunctive PD medications, including dopamine agonists,MAO-B inhibitors, and anti-cholinergics [24]. Thus, otherthan in patients with motor fluctuations, it is not clear thatany class of PD medications has a consistent effect on anx-iety symptoms in PD.

In the general population, panic disorder is reported tobe the least common of anxiety disorders in the elderly,and it is thought that most cases of panic disorder inthe elderly have their onset earlier in adulthood [42]. Inaddition, late-onset panic disorder usually is associatedwith co-morbid psychiatric or medical disorders. Thesefindings in the general population have been referencedto support the hypothesis that the development of panicattacks in a subset of PD patients is due to a sharedneurobiological vulnerability between panic symptomsand PD [1]. The role of dopamine in the developmentof anxiety symptoms in PD is strongest for patients with“off” periods or NMFs. One study of panic attacks inPD found a correlation between panic attacks and ear-lier disease onset, earlier initiation of levodopa therapy,and higher levodopa dosages [10]. In this study, panicattacks occurred nearly always during “off” periods, andthere was a positive correlation between the number of

daily panic attacks, “fragmentation” of levodopa dosages,and number of fluctuations. This study is consistent withother reports of an association between anxiety symptomsand NMFs, particularly during the “off” state [1,4,43].

In general, anxiety symptoms occurring during “off”periods are reported to improve after levodopa intake.In an open-label levodopa infusion study, anxiety lev-els were high pre-infusion (“off” state), improved withinfusion, and then worsened with levodopa wearing off.There was no correlation between improvement in motorfunction (tapping speed) and anxiety improvement, sug-gesting that the anti-anxiety effects of levodopa infusionwere not a psychological response to improved motorfunction [44]. In a subsequent double-blind, placebo-controlled levodopa infusion study, levodopa (but notplacebo) improved both anxiety symptoms and tappingspeed, with improvements in anxiety often precedingimprovement in motor symptoms [45]. Although thereis not always a direct correlation between anxiety symp-toms and “off” periods [34], overall the research suggeststhat NMFs in PD are probably due to the combination ofdopamine depletion and the administration of short-liveddopaminergic drugs, which lead to pulsatile stimulationof striatal dopamine receptors, as has been proposed forthe pathophysiology of motor fluctuations in PD [46].

Other neurotransmittersThe main neurotransmitters implicated in the pathogen-esis of anxiety disorders in primary psychiatric popula-tions are norepinephrine, serotonin, and γ -aminobutyricacid (GABA). Most selective serotonin reuptake inhibitors(SSRIs) and other anti-depressants with serotonergicreuptake inhibition properties also are approved for thetreatment of a range of anxiety disorders, including gener-alized anxiety disorder, panic disorder, social phobia, andOCD. There is also evidence that cholecystokinin (CKK)may be involved in the pathogenesis of panic disorder[47], and that dopamine may have a role in the develop-ment of social phobia [48].

High levels of noradrenergic neuronal activity arerelated to the expression of anxiety and fear, and alsoto the somatic and cardiovascular symptoms that accom-pany panic anxiety states. Clinical investigations ofyohimbine and clonidine, which increase and decrease,respectively, noradrenergic activity have found that panicdisorder patients are more sensitive to their effects thanhealthy controls [49]. The suggestion that the noradren-ergic system has a key role in the development of anx-iety disorders is particularly interesting for PD patients,given the increasing awareness of noradrenergic dysfunc-tion in PD [50], even early in the disease course [51]. Someexperts suggest an interaction between the dopaminergicand noradrenergic systems in the etiology of panic attacksin PD, with falling levels of dopamine in the brain leading



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to a disinhibited firing of the norepinephrine-producinglocus coeruleus, clinically manifested by a panic attack[10].

Alegret et al.’s study of OCD in PD found a correla-tion between duration and severity of disease and anxiety[12]. As only patients with severe PD demonstrated OCDsymptoms, the authors hypothesized that OCD symp-toms in PD are not directly related to the initial nigros-triatal dopaminergic deficiency which causes initial PDsymptoms, but rather involves changes at the level ofbasal ganglia circuitry, including degeneration of cortico-striatal circuitry in the advanced stages of the disease.

Brain regionsIn a PET regional cerebral blood flow (rCBF) study ofPD patients with motor fluctuations, some of whom alsohad NMFs (including anxiety symptoms), CBF was mea-sured pre- and post-levodopa challenge [52]. Patientswith mood fluctuations had decreased blood flow afterlevodopa challenge in several brain regions, including theposterior cingulate cortex and the medial frontal gyrus.The authors concluded that mood fluctuations, includ-ing anxiety, may arise in parkinsonian PD patients whohave abnormal dopaminergic modulation of the caudatenucleus, anterior cingulate cortex, or orbitofrontal cortex,all of which innervate the posterior cingulate cortex, anarea strongly linked to mood and anxiety and with knownrCBF responsiveness to levodopa or D2-like dopaminereceptor agonists.

In an [18F]fluorodopa PET study examining the associ-ation between personality traits and dopaminergic func-tion in PD, the harm-avoidance personality score (asso-ciated with anxiety and depression) was increased in PDpatients compared with healthy controls. In addition, thePD patients’ higher scores on this measure were associ-ated with increased [18F]fluorodopa uptake in the rightcaudate nucleus [53].

GeneticsAlthough there is no published research on the genet-ics of anxiety disorders in PD, indirect evidence for thegenetic underpinnings of anxiety in PD comes from arecent case–control study which found that first-degreerelatives of PD patients had an increased lifetime risk ofboth anxiety (hazards ratio = 1.55, 95% CI = 1.05–2.28)and depressive disorders [54]. These results were primar-ily driven by the relatives of patients with younger ageat PD onset, and held true even after excluding thosePD patients who had experienced depressive or anxietydisorders prior to the onset of their motor symptoms.These findings suggest that anxiety disorders and PD mayshare familial susceptibility factors (either genetic or non-genetic) and common pathogenetic mechanisms.

Assessment and diagnosis

Symptom overlapAs mentioned previously, there is evidence of symptomoverlap between anxiety symptoms and common auto-nomic symptoms in PD [31]. Symptoms such as postu-ral dizziness, frequency of micturition, urinary hesitancy,constipation, dry mouth, impotence, and loss of libido,all reported to occur commonly in PD, were associatedwith measures of anxiety. It is impossible to know if suchsymptoms in PD occur primarily in the context of anautonomic disorder or an anxiety disorder, but the over-lap does highlight complexities in the diagnosis of anx-iety disorders in PD. Symptom overlap has also beenreported for depressive symptoms and core PD symp-toms (e.g., psychomotor retardation, insomnia, weightloss, and fatigue), which led to a proposal for modifieddiagnostic criteria for depression in PD [33]. As part ofthese proposed criteria, a recommendation was made touse an inclusive approach (i.e., counting endorsed itemstowards a diagnosis of depression without trying to ascer-tain the etiology of the symptom) for rating depressivesymptoms in PD, but no such similar recommendationexists for rating autonomic symptoms.

Rating scalesThe Movement Disorder Society (MDS) recently commis-sioned a task force to critique and make recommenda-tions regarding the use of anxiety rating scales in PD [55].A systematic review was conducted to identify anxietyscales that have either been validated or used in patientswith PD. Six anxiety rating scales were identified. Thesewere the Beck Anxiety Inventory (BAI), the Hospital Anx-iety and Depression Scale (HADS), the Zung Self-ratingAnxiety Scale (SAS) and Anxiety Status Inventory (ASI),the Spielberger State Trait Anxiety Inventory (STAI), andthe Hamilton Anxiety Rating Scale (HAM-A). In addition,item 5 of the NPI, which assesses anxiety, was included inthe review.

The task force concluded that no scales met criteria tobe “recommended,” as essential clinimetric informationis missing for all scales. All available anxiety scales tendto focus on symptoms of GAD and panic disorder andnot on other anxiety disorders. However, since these arethe most prevalent anxiety syndromes in PD, this is nota major limitation. Based on the item formulation, timeframe, and clinimetric information, the BAI is more sen-sitive to episodic anxiety disorders, such as panic disor-der, whereas the STAI is more focused towards sustainedanxiety disorders, such as GAD. Since the time frame ofthe “state” subscale of the STAI is “right now,” it maybe assumed that it is not at all sensitive for panic dis-order. Other scales have items that are less differentiallyfocused towards either episodic or sustained anxiety




disorders. A basic clinimetric question that is not lim-ited to PD remains unanswered: can a single scale be reli-able and valid for both episodic and sustained anxietydisorders?

Differential diagnosisTerminologies for several distinct diagnostic categoriesare similar and can create confusion. GAD, panic disorder,social phobia, and OCD are all considered anxiety dis-orders in DSM-IV-TR. A range of impulsive–compulsivebehaviors or disorders have been reported to occur in PD;impulse control disorders (ICDs), which include patho-logical gambling and related disorders reported to occurin PD (e.g., compulsive buying and sexual behavior),comprise a class of psychiatric disorders distinct fromanxiety disorders. Obsessive–compulsive personality dis-order is a pathological personality style characterized by apreoccupation with orderliness, perfectionism, and men-tal and interpersonal control, but does not include specificobsessions or compulsive behaviors that are necessary tomeet criteria for OCD.

DiagnosisThere are DSM-IV-TR criteria for all of the anxiety dis-orders reported to occur in PD, including GAD, panicdisorder, social phobia, and OCD, and the criteria canbe applied informally in a clinical setting or as partof a structured diagnostic interview by a trained rater.Whereas panic attacks apply only to the occurrence of dis-crete episodes of intense fear or discomfort, a diagnosis ofpanic disorder requires both recurrent unexpected panicattacks and at least one of the following: persistent con-cern about additional attacks, worry about the implica-tions or consequences of an attack, or a significant changein behavior related to the attacks. As panic attacks in PDoccurring during “off” periods are often expected, it is notclear if this should preclude a diagnosis of panic disor-der. DSM-IV-TR also specifically states that social phobiashould not be diagnosed in a PD patient if the sole fearrelates to PD symptoms (e.g., tremor) being observed inpublic. Also according to DSM-IV-TR, GAD should notbe diagnosed if the anxiety symptoms occur exclusivelyduring a mood disorder (e.g., major depressive episode),but it is not clear how to determine if the anxiety disorderor the mood disorder is primary.

Treatment

Published researchOne recent double-blind crossover study examined theeffects of immediate and controlled-release levodopa onmood and anxiety in PD patients with and without motorfluctuations. A dosage of levodopa was associated withimprovement in anxiety scores in patients with motor

fluctuations only, with no difference between immediateand controlled-release levodopa [56].

There are no published controlled treatment stud-ies specifically for anxiety disorders in PD that testedeither available anti-anxiety medications (e.g., benzodi-azepines or selective serotonin reuptake inhibitors) ornon-pharmacologic treatments. Most treatment evidencecomes from secondary analyses of anxiety measures indepression treatment studies. For instance, in an open-label trial of citalopram for major depression in PD, onsecondary analysis it was found that anxiety severity (asmeasured by the HAM-A) improved significantly over an8-week course of treatment [57]. In an open-label studyof escitalopram for major depression in PD, there wasa suggestion for improvement in anxiety severity overthe course of treatment, although the mean decrease inHAM-A score was only 22.2% [58]. Overall, there is alack of research to guide clinical decision making, somost recommendations are made on the basis of clinicalexperience.

Regarding non-pharmacologic treatments, an open-label study of treatment-resistant depression in PD foundthat 2 weeks of left dorsolateral prefrontal repetitive tran-scranial magnetic stimulation (rTMS) was associated witha significant decrease in HAM-A scores [59]. In anotherrTMS study for major depression in PD, in which allsubjects also met criteria for an anxiety disorder (panicdisorder, GAD, or social phobia), rTMS was associatedwith trend improvement in both trait and state anxietyon the STAI [60]. In an uncontrolled study of 10–14 ses-sions of cognitive–behavioral therapy (CBT) for majordepressive disorder in PD (including cases unresponsiveto anti-depressant treatment), a significant decrease inSTAI scores was reported both at the end of treatment andat a 1-month follow-up visit [61].

For PD patients with anxiety symptoms in the con-text of dementia, there is preliminary evidence fromopen-label studies that cholinesterase inhibitor treatmentis associated with an improvement in neuropsychiatricsymptoms, including anxiety [62].

Clinical experienceFor patients who experience anxiety as an NMF dur-ing “off” states, PD medication adjustments (shorten-ing the interval between levodopa dosages) or additions(e.g., COMT inhibitors, dopamine agonists, or MAO-Binhibitors) can decrease the duration and severity ofmotor fluctuations, although it is not known if theseadjustments also improve psychiatric symptoms.

Newer anti-depressants [e.g., selective serotonin reup-take inhibitors (SSRIs) and serotonin–norepinephrinereuptake inhibitors (SNRIs)] are approved for the treat-ment of a range of anxiety disorders in the general pop-ulation and, due to their favorable side effect profile and



200 Chapter 18

limited drug–drug interactions, they are commonly usedas a first-line treatment for anxiety symptoms in PD. Itmay take several weeks for treatment effects to occur, andmany patients do not experience significant improvementin anxiety symptoms with anti-depressant treatment. Inaddition, physicians must be cautious regarding the com-bined use of SSRIs or SNRIs with MAO-B inhibitors dueto the potential induction of serotonin syndrome [1].

Despite the common treatment of anxiety symptomswith anti-depressants, anxiety in PD sometimes requirestreatment with benzodiazepines, most commonly lora-zepam, alprazolam, or clonazepam. Lorazepam does notundergo oxidative metabolism by the liver, so dosageadjustments are unnecessary in patients with liver impair-ment. Alprazolam is often perceived by patients asthe most potent benzodiazepine, and is relatively non-sedating compared with other benzodiazepines. Finally,clonazepam has a long half-life that allows daily or twice-a-day dosaging; it is also used in PD patients with rapideye movement behavior disorder (RBD). Benzodiazepinesin PD must be started at a low dosage, titrated upwardsslowly, and used at the lowest possible effective dosage,as possible side effects include sedation, cognitive impair-ment, and gait impairment.

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Parkinson's Disease (Non-Motor and Non-Dopaminergic Features) || Anxiety Syndromes and Panic Attacks