Psychiatric Symptoms in Parkinson's Disease

Current p SYCHIATRY

Psychiatric symptoms in Parkinson’s disease A team approach to successful management

Stephen L. Byrd, MD Mary D. Hughes, MD Assistant professor, Assistant professor, department of psychiatry and health behavior department of neurology

Medical College of Georgia, Augusta

How can you make sound treatment epression, anxiety, and psychosis are common complications of Parkinson’s disease (PD) and of the decisions when almost no evidence D medications used in antiparkinsonian treatment. These psychiatric problems impair patients’ functioning exists on the use of psychotropics in throughout the course of the chronic degenerative disease. Because medication side effects often call for adjust- patients with Parkinson’s disease? ments and trade-offs in PD treatment, a team effort by the psychiatrist, neurologist, patient, and caregiver is the most A psychiatrist and a neurologist argue effective approach to decision-making. From our experience that collaboration is key to treating PD in such collaborations, here’s what you need to know about PD to be a most-valuable player on that treatment team. patients’ psychiatric symptoms. Presentation of PD The classic triad of PD features consists of a pill-rolling tremor, rigidity, and bradykinesia or slowness of movement. Other common features include postural instability, flexed posture, and other motor-freezing phenomena. continued

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Freezing phenomena occur in the later stages of PD, as levodopa therapy is initiated. Blocking the enzymatic break- the response to dopaminergic therapy becomes erratic and down of dopamine with catechol-O-methyltransferase unpredictable. Freezing can range from hesitation—such as inhibitors is the next therapeutic strategy. when the patient tries to turn or is in a doorway—to transient Within 5 years of starting levodopa therapy 75% of episodes of total inability to move. These episodes are patients experience unsatisfactory motor response, from extremely distressing for both patients and caregivers. unpredictable fluctuations to wearing-off phenomena (in Patients rarely present with the full complement of which a dose of levodopa does not last as long as it once did). symptoms, but the presence of tremor at rest and/or bradyki- Treatment of advanced PD is complicated by the emergence nesia is essential for the diagnosis. While motor signs of psychiatric symptoms, such as hallucinations and dominate the presentation, cognitive symptoms such as short- psychosis, as dopamine levels are increased in an attempt to ened attention span, visuospatial impairment, personality smooth the motor response. changes, and dementia are also frequently present. The significantly distressing level of disability associated Average age of diagnosis is 60, and more men are with the prominent side effects of pharmacologic treatment affected than women (male-to-female ratio is 3:2). Many has led to interest in surgical interventions. These range from causative factors—including genetics and environmental tox- pallidotomy to implantation of basal ganglia stimulators to ins—have been implicated, but the disorder’s etiology transplantation of fetal striatal neurons. The possibility of remains unknown. neuroprotection has also been extensively investigated, with mixed results. Drug treatment side effects PD results from the loss of neurons in the substantia nigra Psychiatric complications of PD that produce the neurotransmitter dopamine. Pharmacologic Depression. Clearly, the stress of anticipating and coping with treatment emphasizes dopamine replacement, dopamine a relentless degenerative disease helps to trigger depression receptor stimulation, or prevention of enzymatic breakdown and anxiety in patients with PD. Depression is the most com- of dopamine in the synaptic cleft. As treatment of PD is symp- mon psychiatric syndrome, with prevalence in PD as high as tomatic and not curative, medications are instituted only 42%.1 Patients with a history of depression are at particular when the disease begins to cause functional impairment. risk.2 Those with recent deterioration or advancing severity of Treatment begins with dopamine agonists (Table). As PD, akinesia, history of falls, or cognitive impairment are also dopamine agonist monotherapy becomes less effective, at increased risk for depression. continued on page 27

Table MEDICATIONS COMMONLY USED IN MANAGING PARKINSON’S DISEASE

Medication class Example Indication for use

MAO-B inhibitor Selegiline ? Neuroprotection

Anticholinergic agents Trihexyphenidyl, benztropine, biperiden, Tremor hyoscyamine, diphenhydramine

Dopamine agonist Pramipexole, pergolide, ? Neuroprotection ropinirole Treatment of movement disorder

Dopamine replacement Carbidopa-levodopa Treatment of movement disorder

Catechol-O- Entacapone, tolcapone Smooth motor fluctuations methyltransferase inhibitor

24 Current VOL. 1, NO. 9 / SEPTEMBER 2002 p SYCHIATRY Parkinson’s disease Current p SYCHIATRY

continued from page 24 Depression correlates well with the patient’s perception Psychotic symptoms can occur with or without the of his or her degree of PD-related disability. Depression symp- clouded sensorium characteristic of delirium. Psychotic toms seem to peak early in the illness following diagnosis and symptoms with an associated confusional state can be associ- in advanced disease.3 ated with use of anticholinergic agents and drugs such as Patients may present with symptoms meeting diagnostic selegiline and amantadine.17 Catechol-O-methyltransferase criteria ranging from dysthymic disorder to minor depression inhibitors cause more sustained dopaminergic activity of lev- to major depressive disorder.1,4 Although they will frequently odopa, which can result in psychotic symptoms. Therefore, endorse suicidal ideation, patients with PD have a low rate of the use of all known classes of antiparkinsonian medications suicide. Diagnosing depression, however, may be difficult has been associated with drug-induced psychosis. because its symptoms overlap with those of the underlying In advanced PD, paranoid delusions, delusions of neurologic disease: spousal infidelity, and visual hallucinations are common, • Diminished affect and psychomotor slowing may be whereas negative symptoms and thought disturbances are secondary to the motor features of parkinsonism. not.18 Psychosis may be a more important contributor to care- • Diminished concentration giver distress than the motor symptoms of PD and may be may be secondary to cognitive more likely than any other factor to lead to decline rather than depression. nursing home placement of the PD patient Patients also frequently have a chief All known classes (Box 1).15 complaint of diminished energy or fatigue that of antiparkinson’s should trigger further investigation into other medications can Psychiatric interventions depressive symptoms.4,5 cause drug-induced Goals for psychiatric treatment of depres- In addition to the obvious additional suffer- psychosis sion, anxiety, and psychosis associated with ing it causes, depression in PD predicts impaired PD seem relatively straightforward: social, physical, and role functioning.6 Depression •improvement or remission of psychiatric in the PD patient also results in higher distress symptoms for caregivers.7 In one study, depression was • restoration of optimal patient functioning. identified as a risk factor for development of psychosis in PD Ideally, these goals would be achieved without causing patients.8 sedation, orthostatic hypotension, or exacerbating motor Anxiety is a frequent problem for PD patients, with a preva- symptoms. The older age of patients and the progressive lence of 33 to 40%.9,10 Anxiety in PD typically presents with nature of this neurodegenerative disorder predispose patients symptoms of panic disorder, generalized anxiety disorder, or to cognitive side effects. Unfortunately, despite the high social phobia.11 It is comorbid with depression in up to 92% of prevalence of psychiatric disturbances in PD, evidence with cases and— like depression—frequently predates the onset of which to evaluate treatment efficacy and safety and to guide motor symptoms.12 treatment selection is extremely limited. Anxiety symptoms have been correlated, although not For depression associated with PD, extensive clinical experi- consistently, with the on-off motor phenomenon often found ence supports the efficacy of tricyclic antidepressants. Even in advanced PD.13 They can also be an adverse effect of many so, selective serotonin reuptake inhibitors (SSRIs) are the of the antiparkinsonian medications, including anticholiner- preferred treatment, although only open-label trials and case gics, dopamine agonists, catechol-O-methyltransferase reports support their efficacy.5,12 Compared with tricyclics, inhibitors, and selegiline. Both anxiety and depression have SSRIs exhibit a relative lack of problems with sedation, ortho- been associated with an increased risk for falls.14 static hypotension, and memory-impairing anticholinergic Psychotic symptoms. Up to 25% of PD patients experience side effects. While case reports have cited worsening of motor delusions or hallucinations.15 Risk factors include dementia, symptoms with SSRIs, a recent prospective study found no sleep disturbance, and—most commonly—the use of significant worsening of PD symptoms during treatment dopaminergic agents. Up to one-fifth of patients using with citalopram, fluoxetine, fluvoxamine, or sertraline.19 Co- dopaminergic drugs experience psychotic symptoms.16 administration of an SSRI with selegiline is not absolutely

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first-line pharmacotherapy. Benzodiazepines should Box 1 be used cautiously, as they increase the risk of falls, CASE REPORT: A downward spiral sedation, and confusion in older patients. One small controlled study found that buspirone was well toler- r. J had a 6-year history of PD with pronounced bradykine- ated in PD patients at low dosages (10 to 40 mg/d), Msia and gait disturbance treated with amantadine and car- but anxiety did not improve. At high dosages (100 bidopa-levodopa. His rigidity began to worsen, so the dosage mg/d), anxiety worsened.21 of carbidopa-levodopa was increased. His wife then reported Psychosis. Data on use of antipsychotic agents in PD that he had increased confusion and balance problems. On are also limited, but some evidence supports their use evaluation, he was found to have a urinary tract infection. in treating PD-related psychotic symptoms. While Following antibiotic treatment, mental status and gait returned conventional antipsychotics can help control psy- to usual baseline. chosis, the potential is high for worsening of parkin- One year later, Mr. J began having trouble getting out of sonian symptoms due to D2 receptor blockade. bed, with unpredictable motor freezing episodes. Pramipexole Among the atypical antipsychotics, clozapine was added to his regimen, and he began having prominent has been most extensively studied in PD and has visual hallucinations. Low-dose trifluoperazine was added, and been shown in open and double-blind trials to be hallucinations improved. The patient became increasingly effective and well tolerated at low dosages (6.25 to 50 depressed, and sertraline was started. mg/d). A limited number of open studies of some of Over the next year, his function progressively worsened, the newer atypicals have been performed. While with increased motor freezing and unpredictable dyskinesias. extreme caution must be used in comparing data Hallucinations complicated attempts to change his medica- from these studies due to highly variable dosing and tions. Amantadine was stopped without improvement. He was other study design issues, clozapine and quetiapine referred for surgical evaluation, but because of his cognitive appear to be the agents best tolerated by PD status and depression was deemed not to be a candidate. patients.12,18,22 Initial antipsychotic dosing should be He began to fall repeatedly and developed orthostatic low and escalation cautious—regardless of the hypotension. His clinical course continued to be complicated agent chosen—because of the dose-related poten- by hallucinations and delusions that his wife was being tial for worsening of parkinsonian symptoms, seda- unfaithful. Ongoing psychosis and severe gait instability led tion, and orthostatic hypotension. to his admission to a nursing home.

A team approach to treatment contraindicated, but the combination does carry a very small Because psychiatric and PD symptoms and treatments are risk of development of serotonin syndrome.1,5 closely interrelated, the psychiatrist, neurologist, patient, and Data are even more scant on the safe use of other antide- caregiver must collaborate for the best therapeutic result. pressants in PD. Electroconvulsive A simplistic approach to treatment can result in a therapy has been proven helpful in catastrophic downward spiral in patient refractory cases and sometimes results in ECT can be helpful in functioning. transient motor symptom improvement.1,5,12 Often, compromises must be made While clinical experience suggests that psy- refractory depression between optimal control of parkinsonian chotherapy frequently helps, no extensive con- and sometimes and psychiatric symptoms to achieve the trolled studies exist. One small study suggests the improves motor best overall patient function. Patients and efficacy of structured cognitive psychotherapy.20 symptoms transiently caregivers must be counseled about possi- Anxiety. No studies have examined the treatment of ble psychiatric symptoms associated with anxiety in PD patients. Given the extremely high PD and antiparkinsonian therapy, as well comorbidity of anxiety with depression, antide- as the potential for adverse effects from psychiatric med- pressants should probably be considered as a ications. With this knowledge, patients and caregivers can

28 Current VOL. 1, NO. 9 / SEPTEMBER 2002 p SYCHIATRY Current p SYCHIATRY

help assess the severity of symptoms and set Box 2 treatment priorities, depending on how CASE REPORT: Panic attacks or hallucinations? symptoms may be affecting the patient’s level of functioning. For example, if an effec- rs. K had a 4-year history of rapidly progressing PD treated tive antiparkinsonian regimen has triggered Mwith entacapone, carbidopa-levodopa, and a deep brain stim- infrequent, nondistressing hallucinations ulator. Increasing periods of motor freezing, which were often with preserved insight, intervention may not accompanied by panic attacks, led her to become increasingly be required beyond patient and caregiver depressed and demanding of her caregiver husband. Eventually, education (Box 2). she was admitted to an inpatient psychiatry unit because of Patient workup. When intervention is suicidal ideation. required for psychiatric symptoms, it should After a neurologic evaluation, the dosing times of her begin with careful neurologic evaluation. carbidopa-levodopa and entacapone were changed, but she Triggering factors such as infections (com- continued to have panic attacks and remained depressed. monly urinary tract infections and pneumo- Alprazolam promptly reduced her panic symptoms, and paroxetine nia), metabolic disorders (hyperglycemia, was initiated for depression. A discussion with the patient and her hypothyroidism), subdural hematomas (if the husband revealed that they had some longstanding issues in their patient is falling), and drug interactions marriage that were exacerbated by Mrs K’s increasing dependen- should be ruled out or appropriately cy. The couple was referred for marital therapy, and Mrs. K agreed addressed. to begin attending a senior center. Next, try to sequentially eliminate Following discharge, the panic remained controlled and antiparkinsonian medications until the psy- depression improved. Entacapone was replaced with tolcapone to 23 chosis resolves or motor function worsens. see if motor freezing would decrease. Mrs. K’s movements Because of considerable overlap between PD improved, but her husband reported she had awakened on several symptoms and depression (psychomotor retar- nights with visual hallucinations. The hallucinations were infre- dation, fatigue, and anergia), optimizing PD quent, unaccompanied by agitation, and not distressing to the therapy sometimes can result in substantial patient. Following a discussion of therapeutic options with Mrs. K psychiatric improvement. Some evidence also and her husband, antipsychotic therapy was not instituted. The suggests that the dopamine agonist pramipex- patient continues to live at home and attends the senior center ole may be effective in treating both PD and regularly. depression.5 When psychiatric medications are neces- sary for depression, anxiety, or psychosis, carefully review tar- important to monitor the impact of psychiatric symptoms and get symptoms, treatment expectations, and possible adverse PD on the patient’s caregiver. Frequently assess whether the effects with the patient and caregiver. Keep in mind the pro- caregiver and patient have adequate social supports, and gressive nature of PD and, in addition to frequent monitor- address any emerging needs. Useful interventions include ing, educate and encourage caregivers to immediately report caregiver counseling, referrals to support groups, and respite any suspected adverse effects. care.24 Any motor function deterioration should trigger a References re-evaluation of psychotropic medications before you pre- 1. Slaughter JR, Slaughter KA, Nichols D, et al. Prevalence, clinical manifestations, eti- sume that the patient’s PD is progressing. Because ology, and treatment of depression in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2001;13:187-96. antiparkinsonian drug regimens change over time, review the 2. Starksein SE, Preziosi TJ, Bolduc PL, Robinson RG. Depression in Parkinson’s disease. J Nerv Ment Dis 1990;178:27-31. patient’s medications at each appointment, and alert patients 3. Schrag A, Jahanshahi M, Quinn P. What contributes to depression in Parkinson’s and caregivers to potential psychiatric complications of any disease? Psychological Medicine 2001;31:65-73. 4. Poewe W, Luginger E. Depression in Parkinson’s disease: impediments to recogni- new medication. tion and treatment options. Neurology 2001;52(7):S002-S006. Caregiver treatment In addition to treating the patient, it is continued on page 35

VOL. 1, NO. 9 / SEPTEMBER 2002 29 3 RichardIH,JustusAW, Kurlan Relationshipbetweenmoodandmotorfluctua- R. 13. 2 MenzaMA.Psychiatric aspectsofParkinson’s disease. 12. 1 RichardIH,SchiffeRB,Kurler AnxietyandParkinson’s R. disease. 11. Walsh K,BennettG.Parkinson’s diseaseandanxiety. 10. continued frompage29 .ShulmanLM,Taback RL,BeanJ,Weiner WJ.Comorbidityofthenonmotorsymp- 9. .GiladiN,Treves TA, Paleacu D,etal.Riskfactorsfordementia,depressionandpsy- 8. AarslandD,LarsenJP, etal.MentalsymptomsinParkinson’s diseaseareimportant 7. ColeSA,Woodard JL,JuncosJL.DepressionanddisabilityinParkinson’s disease. 6. OkunMS,Watts RL.DepressionassociatedwithParkinson’s disease:clinicalfea- 5. Amantadine Fluvoxamine Citalopram Entacapone Alprazolam Clozapine Buspirone Carbidopa-levodopa Biperiden Benztropine DRUG BRANDNAMES are mentionedinthisarticleorwithmanufacturersofcompetingproducts. The authorsreportnofinancialrelationshipwithanycompanywhoseproducts DISCLOSURE tions inPD. 104. Clin Neurosci 2001;77(904):89-93. toms ofPD. chosis inlong-standingParkinson’s disease. contributors tocaregiverdistress. tures andtreatment. Neuropsychiatry ClinNeurosci lines. for themanagementofParkinson’s disease2001:treatmentguide- Olanow CW, Watts RL,Koller WC.Analgorithm(decisiontree) National Parkinson Foundation: http://www.parkinson.org American Parkinson DiseaseAssociation:http://apdaparkinson.com Parkinson’s DiseaseFoundation: http://www.pdf.org Related resources • • • • Akineton • Clozaril Neurology Buspar • • • • Celexa Xanax Comtan Cogentin Symmetrel Luvox Mov Disord J NeuropsychiatryClinNeurosci 1996;8(4):383-92. • Sinemet Neurology 2001;56:5(suppl):S1-S88. 2001;16(3):507-10. • Stick toasingletopic,narrowly focused. Stick • To submit a winning Pearl. will receiveanattractiveplaquemounted withthe year’s winner—tobeannouncedinJanuary2003— enter youinourPearloftheYear competition.This If yourPearlispublished,we’llsendyou$75and made adifference. clinical scenario,oranadjustmentintreatmentthat oft-missed diagnosis,tipsfordealingwithadifficult Current Psychiatry 1996;8(1):20-5. 2002;58:1(suppl):S63-S70. Int JGeriatrPsychiatry A tributetoyour clinicalexpertise Tolcapone Trifluoperazine Sertraline Pergolide Hyoscyamine Selegeline Paroxetine Ropinirole Trihexyphenidyl Pramipexole 2001;13(1):35-41. J NeuralTransm Current Psychiatry wants yourPearls—cluestoan • Postgrad MedJ • • • • • Psychiatric Ann Permax Zoloft Tasmar Requip 1999;14(10):866-74. Eldepryl Paxil • • Mirapex • Levsin • Stelazine 2000;107(1):59-71. Artane J Neuropsychiatry 2002;32:99- Pearl: J 5 Wolters EC,BerendseHW. ManagementofpsychosisinParkinson’s disease. 15. AshburnA,StackE,PickeringCM,Ward CD.Acommunity-dwelling sampleof 14. 7 Wolters EC.DopaminomimeticpsychosisinParkinson’s diseasepatients. 17. Juncos,JL.ManagementofpsychoticaspectsParkinson’s disease. 16. 4 EllgringJH.Depression,psychosis,dementia:impactonthefamily. 24. 8 Friedman JH,Factor SA.Atypical antipsychoticsinthetreatmentofdrug-induced 18. 3 OlanowCW, Watts RL,Koller WC. Analgorithm(decisiontree)forthemanagement 23. Tarsy D,BaldessariniRJ,Tarazi FI.Effectsofnewerantipsychoticsonextrapyrami- 22. 1 LudwigCL,Weinberger G,etal.Buspirone,Parkinson’s Bruno diseaseandthe DR, 21. 19. Dell’Agnello G, Ceravolo R, et al. SSRIs donotworsenParkinson’s etal.SSRIs Dell’AgnelloG,CeravoloR, disease:evidence 19. 0 DreisigH,BeckmannJ,Wermuth cogni- L,etal.Psychological effectsofstructured 20. 2001;30(1):47-52. people withParkinson’s disease:characteristicsoffallersandnon-fallers. 1999;60:8(suppl):42-53. Opin Neurol 1999;52:7(suppl 3):S17-S20. S88. Parkinson’s disease. 1999;52:7(suppl):S010-S013. of Parkinson’s disease2001:treatmentguidelines. dal function. locus ceruleus. locus ceruleus. from anopen-label,prospectivestudy. Psychiatry tive psychotherapyinyoungpatientswithParkinson’s disease(abstr). can achievetheoptimumtherapeuticresult. psychiatrist, neurologist,patient,andcaregiver are oftenrequired.Working together, the psychiatric symptoms,treatmentadjustments interrelationship betweenPD’s neurologicand disease anditstreatment.Becauseofthe common complicationsofParkinson’s D epression, anxiety, andpsychosisare 1999;53(3):217-21. (201) 782-5704. of asubmittedPearl? Questions aboutPearlguidelinesor thestatus [email protected]. • Provide yourfullname,address,phonenumber, • Limitreferencesto2-3. • Keepthelengthto600words. • suretheinformationappliestomost Make • 2001;14(4):499-504. CNS Drugs Clin Neuropharmacol (for payment),andtypeofpractice. e-mail address,SocialSecuritynumber psychiatric practices. Mov Disord 2002;16(1):23-45. VOL. 1,NO. 9/SEPTEMBER 2002 2000;15(2):201-11. 1986;9(4)373-8. Clin Neuropharmacol Contact PeteKelly at Neurology Bottom Current 2001;24(4):221-27. 2001;56:5(suppl):S1- p SYCHIATRY Neurology J ClinPsychiatry Nordic J Age Ageing Neurology Curr 35 Line