Parkinson Disease: Phenomenology and Treatment of the Most Common Psychiatric Symptoms

Parkinson disease (PD) is a progressive neurodegenerative disorder that is characterized by its motor signs, including resting tremor, rigidity, bradykinesia, and postural instability. PD is more common in the elderly, and there is usually no family history of the disease. The cause of PD is unknown but involves the loss of dopamine in the substantia nigra and striatum, and the presence of Lewy body neuronal inclusions. PD is diagnosed clinically, with definitive diagnosis obtained at autopsy. In atypical clinical presentations, MRI can be helpful in detecting other causes, such as vascular parkinsonism. Functional neuroimaging, such as single photon emission computed tomography and positron emission tomography, is primarily used in research and not in routine clinical work because of its high cost and restricted availability.

Familial PD occurs in young people and is linked to both autosomal dominant and recessive "PARK" genes. Although important for insight into the molecular pathogenesis of PD and therapeutics, genetic testing for mutations is thus far of little clinical use. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a by-product of the synthesis of meperidine used in synthetic heroin, is the only environmental agent directly linked to parkinsonism. Cigarette smoking and habitual caffeine intake may lessen the risk of parkinsonism, but the mechanism of this effect is not known. Treatment of PD is aimed at reducing motor symptoms with dopamine replacement therapy.

Although PD is primarily a movement disorder, psychiatric disturbances are prevalent and include depression, anxiety, psychosis, and dementia. The psychiatrist has an important role in treating PD patients because the behavioral aspects of PD are frequently more disabling than the motor symptoms and often complicate the course of the disease. This review will focus on the phenomenology and treatment of the most common psychiatric disturbances in PD.

Depression

Depression is one of the most common psychiatric conditions in PD, occurring in 40% to 50% of patients.¹ Minor depression and dysthymia account for a large proportion of symptoms.¹ Despite its high prevalence, PD depression is frequently undiagnosed.² This may be due in part to the difficulty of recognizing depression in PD because depressive symptoms often mimic those of PD (such as flat affect, psychomotor retardation, fatigue, weight loss, sleep disturbance, and decreased libido). PD depression may also present differently from primary major depression, with less sadness, anhedonia, and guilt but with greater anxiety, pessimism, and decreased concentration.^1,3,4 Depression may occur at any stage of PD and can precede the development of motor symptoms.¹

The cause of depression in PD is unknown but may involve neuronal loss and a reduction in serotonin, norepinephrine, and dopamine.⁵ PD depression may also represent a reaction to having an incurable and debilitating disease. In a study comparing PD patients with patients who have rheumatoid arthritis, depression was found to occur with equal frequency in both groups and was related to the severity of illness and functional disability.³

It is important to identify depression early in PD because it leads to more rapid cognitive decline,⁶ greater motor disease severity,³ and disability.^3,6 In our study, we found that the severity of depression was a significant risk factor for sleep disturbance in PD patients.⁷ It is recommended that PD patients be screened regularly for depression. The Geriatric Depression Scale and Hamilton Rating Scale for Depression are validated in the PD population⁸ and can be used to monitor treatment response.

Controlled studies examining the efficacy of antidepressants in PD depression are lacking. A meta-analysis found no difference between active treatment and placebo in PD depression.⁹ The American Academy of Neurology (AAN) Practice Parameter on the treatment of depression, psychosis, and dementia in PD has recommended that amitriptyline be considered in the treatment of PD depression but because of its adverse-effect profile, this may not necessarily be the first-choice antidepressant.¹⁰ The AAN report concluded that there was insufficient evidence to make other recommendations.¹⁰

Open-label trials with SSRIs in PD suggest a beneficial effect on depression. However, to date, the efficacy of SSRIs in the treatment of PD depression has not been demonstrated since the 2 placebo-controlled trials yielded negative findings.^11,12 In the studies, despite treatment effects in both the citalopram and sertraline groups, there were no statistically significant differences in response rate between treatment and placebo.^11,12 However, the studies were limited by insufficient power. Most PD patients tolerate SSRIs without worsening of PD,but caution should be observed when using SSRIs or tricyclic antidepressants (TCAs) in combination with selegiline or rasagiline because of the risk of serotonin syndrome.

As is the case for the general population, the SSRIs are recommended as first-choice antidepressants for PD patients because they are well tolerated, with few adverse effects and drug-drug interactions. Other possible first-line antidepressants include venla-faxine, duloxetine, mirtazapine, and bupropion; however, clinical trials demonstrating their efficacy in PD depression are lacking. In addition to treating depression, mirtazapine can improve tremor and levodopa (l-dopa)-induced dyskinesias in patients with PD.¹³ Because of its dopaminergic activity, bupropion may precipitate psychosis in PD patients. Since most PD patients are elderly, they may be susceptible to the adverse effects of TCAs, such as orthostatic hypotension, worsened cognition, and cardiovascular effects. Thus, TCAs are recommended as second-line antidepres- sants. However, low doses of TCAs may be beneficial in some patients with PD to reduce drooling, inhibit an overactive bladder, and treat insomnia.

Antiparkinsonian medications, including selegiline, bromocriptine, pergolide, and pramipexole, are reported to have antidepressant effects.^14-16 Electroconvulsive therapy is beneficial in patients with medication-refractory depression and usually improves motor function.¹⁷ Psychotherapy may be helpful in patients with PD who have mild depression and can be used to augment treatment response to pharmacotherapy.

Anxiety

Anxiety disorders occur in up to 40% of PD patients,¹⁸ compared with 5% to 15% of the general population.¹⁹ The most common anxiety disorders in PD are panic disorder, generalized anxiety disorder, and social phobia.^18,19 Although anxiety is reported to occur after diagnosis of PD,¹⁸ a case-control study found that anxiety disorders were significantly associated with subsequent PD and were present for up to 20 years before onset of motor symptoms.²⁰ Anxiety is reported to occur in patients who experience motor fluctuations, especially during the "off" phase, when antiparkinsonian medication wears off.^21,22 Alterations in serotonin and norepinephrine are believed to play important roles underlying anxiety.²¹ There is no consensus on whether medications used to treat motor symptoms in PD are responsible for anxiety symptoms. While an increase in panic attacks in patients on l-dopa therapy has been reported,²¹ other studies found no association between antiparkinsonian medication and anxiety.^22,23 One controlled study found that l-dopa produced a dose-related reduction in anxiety and elevation of mood.²³

There are no randomized controlled trials of anti-anxiety medication in PD. When evaluating the anxious patient who has PD, it is impor- tant to assess the timing of anxiety, particularly whether it is related to the "off" period, in which case, treatment involves adjustment of antiparkinsonian medications. The SSRIs are first-choice medications, and high doses may be necessary to treat anxiety symptoms. Low doses of short-acting benzodiazepines may be needed initially while the optimal response of the SSRI is attained. However, benzodiazepines should be used with caution because most patients with PD are elderly and susceptible to falls, and there is a risk of dependence. The serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, may be effective in treating anxiety, but there are no data on their efficacy in the PD population. Buspirone has been used in PD, but its efficacy is not apparent.²⁴ Cognitive-behavioral therapy may have a role in treating anxiety in PD patients.

Psychosis

Psychosis is not considered to be a primary symptom of idiopathic PD but occurs in medication-treated patients with PD. Psychosis can also occur as part of a delirium or in patients with dementia. Patients who have PD with psychosis have an increased rate of nursing home placement and an increased mortality rate.²⁵ Up to 40% of patients with PD are reported to have psychotic symptoms-most commonly, visual hallucinations.²⁵ Hallucinations differ from those in primary psychotic disorders in that the images usually lack emotional content and most patients retain insight into the unreality of the image. Hallucinations are typically of people but also include animals, and they generally occur in low-stimulus environments. Most patients are not bothered by the hallucinations, and treatment is not usually required.

Patients with dementia often lack insight into their psychosis and, as a result, may become agitated, in which case treatment is required. Delusions occur in 5% to 10% of patients who have PD,²⁶ and they often develop in the setting of hallucinations. All types of delusions occur with relatively equal frequency.²⁷

Managing psychosis in PD is often complex and challenging, in part because antipsychotic medication can adversely affect motor function while dopaminergic medication used to treat PD can worsen psychosis. Typical antipsychotics often worsen parkinsonism. Among atypical antipsychotics, clozapine and quetiapine are the only agents reported to be free of motor adverse effects. Two multicenter, double-blind, placebo-controlled trials found that the most effective antipsychotic dosage of clozapine was only 6.75 mg at bedtime,^28,29 a dose lower than that administered in the psychiatric population. The potential adverse effect of agranulocytosis is not dose-related and, thus, requires the same white blood cell count monitoring rules as for higher doses. This limits the use of clozapine, and it is generally not used as a first choice antipsychotic in patients with PD.

Quetiapine is widely used to treat psychosis in PD on the basis of positive open-label findings and its ease of use compared with clozapine. However, 2 recent double-blind, placebo-controlled trials found no significant antipsychotic benefit.^30,31

The other atypical antipsychotics have had negative effects on motor function in patients with PD. Risperidone has not been adequately tested but has been reported to cause worsening of parkinsonism even at low doses.³² Three double-blind, placebo-controlled trials found that olanzapine caused a significant worsening of motor function and did not improve psychosis.^33,34

Data on ziprasidone are conflicting; the largest of these studies (N = 43) did not reveal worsening of motor skills on ziprasidone,³⁵ but other reports describe significant motor decline in some patients.^36,37 Although aripiprazole is considered to be a partial dopamine agonist, it has been reported to cause motor worsening, even at a dosage of less than 5 mg/d, as well as worsened psychosis.³⁸ The AAN Practice Parameter report recommended that clozapine and quetiapine, but not olanzapine, be considered for treatment of psychosis in PD.¹⁰

The cholinesterase inhibitor, rivastigmine, is effective in reducing hallucinations and delusions in PD patients with dementia.³⁹ Because the onset of the antipsychotic effect of cholinesterase inhibitors can take several weeks, neuroleptics may be required initially to control symptoms.

When evaluating a patient with PD who is psychotic, clinicians should rule out delirium and exclude infections, metabolic disturbances, and psychoactive medications as contributing causes for the psychosis. Anticholinergic medication should be eliminated first, followed by amatadine, monoamine oxidase inhibitors, dopamine agonists, catechol-O-methyltransferase inhibitors, and then reduction in l-dopa dosage. If a reduction in medications is not possible because of risk of worsened motor function, low-dosage quetiapine (12.5 to 25 mg at bedtime) should be initiated and titrated upward as tolerated. If this is not effective, then clozapine should be introduced (6.25 or 12.5 mg at bedtime). Cholinesterase inhibitors should be implemented in patients with comorbid dementia.

Dementia

A recent systematic review found that 24% to 31% of patients with PD had dementia.⁴⁰ Advanced age, hallucinations, and greater motor disease severity correlated with an increased risk for dementia.⁴¹ PD dementia is characterized as a subcortical dementia in which executive function, attention, psychomotor speed, visuospatial skills, and delayed recall are disrupted. In contrast to Alzheimer disease (AD), a cortical dementia, recognition memory and language often remain intact. PD dementia is often difficult to distinguish clinically from dementia with Lewy bodies (DLB), a dementing illness characterized by parkinsonism, visual hallucinations, and fluctuating cognition. Many researchers believe PD dementia and DLB are on the same continuum based on their similar clinical and pathological features.⁴² However, current criteria dictate that PD dementia should be diagnosed in patients with idiopathic PD in whom dementia develops later, whereas DLB should be diagnosed in patients whose cognitive impairment occurs concurrently or before the onset of parkinsonism.⁴²

Dementia in PD has been associated with acetylcholine depletion⁴³ and pathological changes of AD (amyloid plaques and neurofibrillary tangles).⁴⁴ More recently, it has been reported that the degree of Lewy body pathology (Lewy bodies and Lewy neurites) correlated better with PD dementia than with AD pathology.⁴⁵

Because dementia is a significant predictor of nursing home placement,⁴⁶ it is important for clinicians to identify and treat PD dementia as early as possible. Routine questioning about the patient's ability to be independent in activities of daily living, such as driving and managing finances, can assess for status of cognition. Neuropsychological testing often identifies early cognitive deficits in PD that may not be apparent in a clinical interview. Screening tools for dementia have not yet been validated in the PD population.

Of the cholinesterase inhibitors that are FDA-approved for AD (tacrine, donepezil, rivastigmine, and galantamine), only rivastigmine is approved for PD dementia. The approval was based on a large double-blind, placebo-controlled 24-week trial of PD patients with dementia who demonstrated a significant improvement when given rivastigmine compared with placebo.³⁹ This effect was maintained at week 48 in a treatment extension study.⁴⁷ Although rivastigmine is the only FDA-approved medication for the treatment of PD dementia, other cholinesterase inhibitors may be effective as well. Two double-blind, placebo-controlled trials found do- nepezil to be beneficial for PD patients with dementia.^48,49

Overall, the treatment effects of riv-astigmine and donepezil on cognition in PD are small and probably similar to the effects seen in AD. The AAN Practice Parameter report recommends that both rivastigmine and donepezil be considered for the treatment of dementia in PD.²⁰

Conclusion

PD is increasingly being recognized as a neuropsychiatric disease with significant behavioral symptoms. It is important for psychiatrists and neurologists to collaborate in treating patients with PD because management of PD is optimal when the psychiatric and cognitive aspects are considered along with the motor deficits. When treating the behavioral symptoms of PD, psychiatrists should be familiar with potential motor adverse effects of medication. Early recognition of the psychiatric disturbances of PD can reduce morbidity and improve the quality of life of patients with PD.

References:

References

1.

Cummings JL. Depression and Parkinson's disease: a review.

Am J Psychiatry.

1992;149:443-454.

2.

Shulman LM, Taback RL, Rabinstein AA, Weiner WJ. Non-recognition of depression and other non-motor symptoms in Parkinson's disease.

Parkinsonism Relat Disord.

2002;8:193-197.

3.

Gotham AM, Brown RG, Marsden CD. Depression in Parkinson's disease: a quantitative and qualitative analysis.

J Neurol Neurosurg Psychiatry.

1986;49: 381-389.

4.

Ehrt U, Bronnick K, Leentjens AF, et al. Depressive symptom profile in Parkinson's disease: a comparison with depression in elderly patients without Parkinson's disease.

Int J Geriatr Psychiatry.

2006;21:252-258.

5.

McDonald WM, Richard IH, DeLong MR. Prevalence, etiology, and treatment of depression in Parkinson's disease.

Biol Psychiatry.

2003;54:363-375.

6.

Starkstein SE, Mayberg HS, Leiguarda R, et al. A prospective longitudinal study of depression, cognitive decline, and physical impairments in patients with Parkinson's disease.

J Neurol Neuurosurg Psychiatry.

1992;55:377-382.

7.

Borek LL, Kohn R, Friedman JH. Mood and sleep in Parkinson's disease.

J Clin Psychiatry.

2006;67:958-963.

8.

Weintraub D, Oehlberg KA, Katz IR, Stern MB. Test characteristics of the 15-item geriatric depression scale and Hamilton depression scale in Parkinson's disease.

Am J Geriatr Psychiatry.

2006;14:169-175.

9.

Weintraub D, Morales KH, Moberg PJ, et al. Antidepressant studies in Parkinson's disease: a review and meta-analysis.

Mov Disord.

2005;20:1161-1169.

10.

Miyasaki JM, Shannon K, Voon V, et al. Practice Parameter: Evaluation and treatment of depression, psychosis, and dementia in Parkinson's disease (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology.

Neurology.

2006;66:996-1002.

11.

Wermuth L, Sorensen P, Timm S, et al. Depression in idiopathic Parkinson's disease treated with citalopram.

Nord J Psychiatry.

1998;52:163-169.

12.

Leentjens AF, Vreeling FW, Luijckx GJ, Verhey FR. SSRIs in the treatment of depression in Parkinson's disease.

Int J Geriatr Psychiatry.

2003;18:552-554.

13.

Pact V, Giduz T. Mirtazapine treats resting tremor, essential tremor and levodopa-induced dyskinesias.

Neurology.

1999;53:1154.

14.

Baronti F, Davis TL, Boldry RC, et al. Deprenyl effects on levodopa pharmacodynamics, mood, and free radical scavenging.

Neurology.

1992;42:541-544.

15.

Jouvent R, Abensour P, Bonnet AM, et al. Antiparkinsonian and antidepressant effects of high doses of bromocriptine. An independent comparison.

J Affect Disord.

1983;5:141-145.

16.

Rektorova I, Rektor I, Bares M, et al. Pramipexole and pergolide in the treatment of depression in Parkinson's disease: a national multicentre prospective randomized study.

Eur J Neurol.

2003;10:399-406.

17.

Moellentine C, Rummans T, Ahlskog JE, et al. Effectiveness of ECT in patients with parkinsonism.

J Neuropsychiatry Clin Neurosci.

1998;10:187-193.

18.

Stein MB, Heuser IJ, Juncos JL, Uhde TW. Anxiety disorders in patients with Parkinson's disease.

Am J Psychiatry.

1990;147:217-220.

19.

Richard IH. Anxiety disorders in Parkinson's disease.

Adv Neurol.

2005;96:42-55.

20.

Shiba M, Bower JH, Maraganore DM, et al. Anxiety disorders and depressive disorders preceding Parkinson's disease: a case-control study.

Mov Disord.

2000; 15:669-677.

21.

Vazquez A, Jimenez-Jimenez FJ, Garcia-Ruiz P, Garcia-Urra D. "Panic attacks" in Parkinson's disease: a long-term complication of levodopa therapy.

Acta Neurol Scand.

1993;87:14-18.

22.

Siemers ER, Shekhar A, Quaid K, Dickson H. Anxiety and motor performance in Parkinson's disease.

Mov Disord.

1993;8:501-506.

23.

Maricle RA, Nutt JG, Valentine RJ, Carter JH. Dose-response relationship of levodopa with mood and anxiety in fluctuating Parkinson's disease: a double- blind, placebo-controlled study.

Neurology.

1995;45: 1757-1760.

24.

Bonifati V, Fabrizio E, Cipriani R, et al. Buspirone in levodopa-induced dyskinesias.

Clin Neuropharmacol.

1994;17:73-82.

25.

Aarsland D, Larsen JP, Cummins JL, Laake K. Prevalence and clinical correlates of psychotic symptoms in Parkinson's disease: a community-based study.

Arch Neurol.

1999;56:595-601.

26.

Factor SA, Molho ES, Podskalny GD, Brown D. Parkinson's disease: drug induced psychiatric states.

Adv Neurol.

1995;65:115-118.

27.

Chou KL, Messing S, Oakes D, et al. Drug-induced psychosis in Parkinson disease: phenomenology and correlations among psychosis rating instruments.

Clin Neuropharmacol.

2005;28:215-219.

28.

Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease.

N Engl J Med.

1999;340:757-763.

29.

Pollak P, Tison F, Rascol O, et al. Clozapine in drug induced psychosis in Parkinson's disease: a randomized, placebo-controlled study with open follow up.

J Neurol Neurosurg Psychiatry.

2004;75:689-695.

30.

Ondo WG, Tinter R, Vuong KD, et al. Double-blind, placebo-controlled unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in Parkinson's disease.

Mov Disord.

2005;20:958-963.

31.

Rabey JM, Prokhorov T, Miniovich A, et al. Effect of quetiapine in psychotic Parkinson's disease patients: a double-blind labeled study of 3 month's duration.

Mov Disord.

2006;22:313-318.

32.

Rich SS, Friedman JH, Ott BR. Risperidone versus clozapine in the treatment of psychosis in six patients with Parkinson's disease and other akinetic-rigid syndromes.

J Clin Psychiatry.

1995;56:556-559.

33.

Ondo WG, Levy JK, Vuong KD, et al. Olanzapine treatment for dopaminergic-induced hallucinations.

Mov Disord.

2002;17:1031-1035.

34.

Breier A, Sutton VK, Feldman PD, et al. Olanzapine in the treatment of dopamimetic-induced psychosis in patients with Parkinson's disease.

Biol Psychiatry.

2002;52:438-445.

35.

López del Val LJ, Santos S. Quetiapine and ziprasidone in the treatment of the psychotic disorders in Parkinson's disease [in Spanish].

Rev Neurol.

2004;39: 661-667.

36.

Gomez-Esteban JC, Zarranz JJ, Velasco F, et al. Use of ziprasidone in parkinsonian patients with psychosis.

Clin Neuropharmacol.

2005;28:111-114.

37.

Schindehutte J, Trenkwalder C. Treatment of drug-induced psychosis in Parkinson's disease with ziprasidone can induce severe dose-dependent off-periods and pathological laughing.

Clin Neurol Neurosurg.

2006;109:188-191.

38.

Friedman JH, Berman RM, Goetz CG, et al. Open-label flexible-dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson's disease.

Mov Disord.

2006;21:2078-2081.

39.

Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson's disease.

N Engl J Med.

2004;351:2509-2518.

40.

Aarsland D, Zaccai J, Brayne C. A systematic review of prevalence studies of dementia in Parkinson's disease.

Mov Disord.

2005;20:1255-1263.

41.

Aarsland D, Andersen K, Larsen JP, et al. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study.

Arch Neurol.

2003;60: 387-392.

42.

Cummings JL.

Third International Workshop on Dementia With Lewy Bodies and Parkinson's Disease Dementia

. Newcastle Upon Tyne, UK; 2003.

43.

Perry EK, Curtis M, Dick DJ, et al. Cholinergic correlates of cognitive impairment in Parkinson's disease: comparisons with Alzheimer's disease.

J Neurol Neurosurg Psychiatry.

1985;48:413-421.

44.

Brown DF, Dababo MA, Bigio EH, et al. Neuropathologic evidence that the Lewy body variant of Alzheimer disease represents coexistence of Alzheimer disease and idiopathic Parkinson disease.

J Neuropathol Exp Neurol.

1998;57:39-46.

45.

Hurtig HI, Trojanowski JQ, Galvin J, et al. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease.

Neurology.

2000;54: 1916-1921.

46.

Aarsland D, Larsen JP, Tandberg E, Laake K. Predictors of nursing home placement in Parkinson's disease: a population-based, prospective study.

J Am Geriatr Soc.

2000;48:938-942.

47.

Poewe W, Wolters E, Emre M, et al. Long-term benefits of rivastigmine in dementia associated with Parkinson's disease: an active treatment extension study.

Mov Disord.

2006;21:456-461.

48.

Ravina B, Putt M, Siderowf A, et al. Donepezil in Parkinson's disease: a randomized, double-blind, placebo-controlled, crossover study.

J Neurol Neurosurg Psychiatry.

2005;76:934-939.

49.

Aarsland D, Laake K, Larsen JP, Janvin C. Donepezil for cognitive impairment in Parkinson's disease: a randomized controlled study.

J Neurol Neurosurg Psychiatry.

2002;72:708-712.