Motor or Mental Control: The Faustian Dilemma in the Management of PD

The prevalence of neuropsychiatric symptoms in patients with Parkinson disease, coupled with the fact that these nonmotor symptoms can be triggered or exacerbated by interventions used in treating motor symptoms, leave clinicians with something of a Faustian dilemma with regard to patient management. In such cases, the benefits of parkinsonian therapy for motor symptoms must be weighed against the potential risks of depression, hallucination, and other neuropsychiatric symptoms—with little in the way of scientific evidence to provide clinical guidance.

Recent developments in the field, however, suggest that management of neuropsychiatric symptoms in patients with Parkinson disease is on its way to becoming more of a science than an art. The Quality Standards Subcommittee of the American Academy of Neurology included evidence-based recommendations for the treatment of depression and psychosis in the set of Parkinson disease practice parameters the subcommittee published in April.¹ And a spate of more recently published and presented studies, not included in the practice parameter review (which included literature published between 1966 and 2004), indicate an increasing emphasis on nonmotor symptoms by Parkinson disease researchers that should ultimately lead to more informed patient management.

VEXING COMPLEXITY

The most frustrating aspect of neuropsychiatric symptoms in patients with Parkinson disease is their variability. Hallucinations have been associated with the use of dopaminergic therapy ^2,3, but some studies have found no association between hallucinations and dopaminergic drug dose,^4,5 and early reports from before the advent of levodopa for treatment of motor symptoms suggest that hallucinations may in some cases result from the disease itself.⁶ Symptoms of depression in patients with PD can not only be variable but can also be difficult to distinguish from symptoms of the disease itself.⁷ Several studies have identified depression as a side effect of subthalamic deep brain stimulation therapy,^8-12 but others have reported no change in depression symptoms following STN-DBS ^13,14 and some have found that depressive symptoms decreased.^15,16 And although depression is more often studied in relation to STN-DBS than antiparkinsonian drug therapy, two studies suggest dopamine agonists may protect against depression.^17,18. Although differences in study design make direct comparisons difficult, the range of findings underscores the complexity of issues involved even in identifying neuropsychiatric complications of PD, much less treating them.

Perhaps it shouldn't be surprising, then, that the strength of the AAN's recommendations for treatment of depression and psychosis in patients with Parkinson disease ranges from level C (possibly effective, ineffective or harmful) to level B (probably effective, ineffective or harmful) – indicating that none of the existing evidence is strong enough to warrant a level A recommendation, which requires the support of at least two prospective, randomized, controlled clinical trials in a representative population. Given the heterogenaiety of the patient population in which neuropsychiatric complications occur, and given the lack of definitive evidence on which to base clinical decisions, experts' advice is to treat each case individually and to not assume anything.

“Any decision regarding Parkinson disease treatment initiation should rely upon a careful weighing of clinical need, expected treatment benefits, and the probability of complicating side-effects,” said Edward C. Lauterbach, MD, professor of psychiatry, neurology and radiology and chief of adult and geriatric psychiatry at Mercer University in Macon, GA, who published a review article on the neuropsychiatry of Parkinson disease last summer in Minerva Medica.¹⁹

PSYCHOSES

For the treatment of psychoses in patients with Parkinson disease, the AAN practice parameter includes level B recommendations for clozapine and against olanzapine, and a level C recommendation for quetiapine.

The cases for clozapine and against olanzapine are persuasive, if not definitive. The clozapine recommendation was based on a randomized, double-blinded, controlled trial published in the New England Journal of Medicine in 1999, which found that 30 PD patients who received a low dose (mean of 24.7 mg per day) of clozapine for four weeks demonstrated significantly greater improvement on three psychosis assessment scales than 30 PD patients who received placebo.²⁰ The recommendation against olanzapine—which has been found to have antipsychotic efficacy in non-PD populations—was based on two studies that compared olanzapine to placebo; researchers from Eli Lilly Research Laboratories and from Baylor College of Medicine separately reported that olanzapine was associated with worsening motor function and did not differ significantly from placebo in terms of psychosis scores after four and nine weeks, respectively.^21,22 Olanzapine has also been associated with increased risk of cerebrovascular adverse events in non-PD patient populations.²³

The subcommittee's case for quetiapine is less conclusive, with the recommendation based on a randomized, open-label comparison of quetiapine with clozapine that was published in 2002.²⁴ In that study, Letterio Morgante, MD, and colleagues from the University of Messina in Italy found that in 11 patients who received quetiapine and 12 who received clozapine, 12-week psychiatric improvements were similar, but that motor symptoms worsened slightly (but not significantly) in the quetiapine patients while improving slightly (and significantly) in the clozapine patients. Although quetiapine, like olanzapine, is an atypical antipsychotic drug, quetiapine was not associated with increased risk of cerebrovascular adverse events in a 2004 study of Alzheimer patients presented at the International Conference on Alzheimer's Disease and Related Disorders and subsequently described by the authors in the Journal of Clinical Psychiatry.²⁵

The recommendations won't surprise most clinicians, among whom there is general consensus that clozapine is the only anti-psychotic therapy for PD patients that is supported by the literature. Most clinicians also note, however, that the well-known risk of agranulocytosis associated with clozapine and the frequent neutrophil count monitoring required as a result of this risk have made alternative therapies like quetiapine more attractive.

“Clozapine is the only well-documented therapy. The problem is the required drug monitoring due to a small risk for agranulocytosis. Thus, it may be problematic for elderly frail or homedwelling patients. Quetiapine is less well documented, but is much used by most clinicians as the first drug, including myself,” said Dag Aarsland, MD, a professor of geriatric psychiatry at Stavanger University Hospital in Stavanger, Norway.

In fact, research on quetiapine has increased since the period reviewed by the AAN subcommittee, with conflicting results. Morgante and colleagues, having expanded their randomized, open-label comparison of quetiapine and clozapine to include 40 patients, found no significant between-group differences at 12 weeks – including, notably, no significant motor changes from baseline in either group.²⁶ But a randomized, double-blinded study performed by William G. Ondo, MD, and colleagues at Baylor College of Medicine, found that 12-week outcomes for 21 patients who received quetiapine were not significantly different from those for 10 patients who received placebo.²⁷

There is also general agreement that one of the first steps in managing psychoses in patients with PD should be to discontinue the use of any anticholinergic medications, which, despite their effectiveness for controlling tremor, are known to be associated with hallucinations and other neuropsychiatric side effects, particularly in elderly patients.²⁸ On the flip side, many clinicians are encouraged by studies suggesting that cholinesterase inhibitors, often used in PD patients for treatment of dementia, may also have anti-psychotic benefits in this patient population.^29-33

“If cognitive impairment is present and hallucinations not too badly tolerated, I would rather use a procholinergic drug such as rivastigmine, as there is some evidence that these drugs may improve hallucinations in this setting. If the hallucinations are not well tolerated (associated with anxiety or behavioral disturbances) and/or not improved by rivastigmine, I would rapidly use clozapine,” said Gilles Fénelon, MD, PhD, a neurologist at Henri Mondor Hospital in Creteil, France; Fénelon noted that quetiapine is not available in France.

Many experts, including Fénelon, Aarsland, and Lauterbach, recommend adjusting antiparkinsonian medications –as tolerated by the patient—before prescribing an antipsychotic drug in response to the development of hallucinations in PD patients. A typical sequence for discontinuation of antiparkinsonian drugs almost always begins with anticholinergics and continues with selegiline, amantadine, dopamine agonists, and catechol-O-methyltransferase (COMT) inhibitors, with levodopa reduction considered last.³ But without conclusive evidence, the question of when to adjust PD therapies and when to start an antipsychotic essentially comes down to personal preference.

“Different clinicians handle it differently,” said Daniel Weintraub, MD, an assistant professor of neurology and psychiatry at the University of Pennsylvania. “Neurologists often place a high value on PD medications and may be more willing to start a psychiatric medication. But there's really not much objective evidence on which to base the decision. We don't even know to what extent the antipsychotics work in Parkinson's patients.”

Recent studies suggesting that antiparkinsonian drug therapy may not be the root cause of hallucinations in PD patients imply that earlier use of antipsychotics, rather than reduction of the antiparkinsonian drugs, should be considered as a first line of treatment. In an Israeli study of 422 patients, no increased risk of hallucinations was associated with levodopa dose or supplementary treatment with amantadine, selegiline, dopamine agonists, entacapone or anticholinergic drugs.⁴ A study of cognitive functioning and hallucination in 128 PD patients, presented in September at the annual meeting of the American Neurological Association, found no association between PD therapy type and hallucination prevalence.³⁴ A 2005 study of 141 patients by Fénelon and colleagues found that, although daily levodopa dose was higher in patients with hallucinations than non-hallucinators, multivariate analysis demonstrated that this factor was not independently predictive of hallucination.⁵ In the French study, three factors were predictive of hallucination onset in PD patients with no history of hallucination: severe sleep disturbances, ocular disorders, and a high axial motor score. Ocular disorders were also found to be predictive of visual hallucination in a Japanese study published in March, which identified visual acuity as a risk factor and suggested that ophthalmologic treatment could reduce or prevent hallucinations.³⁵

All of this discussion regarding treatment of hallucinations, of course, presumes that the hallucinations are adversely impacting a patient's quality of life. Which, Aarsland notes, is not always the case.

“Not all hallucinations need to be treated,” he said. “Some are even pleasurable!”

Determining the cause of psychoses has particular implications for the use of subthalamic deep brain stimulation as an adjunct or alternative to pharmacologic therapy for PD patients. Cognitive decline is considered a contraindication for STN-DBS, so if a patient's psychoses are associated with cognitive decline rather than drug-induced, deep brain stimulation would not be an option, Fénelon said. In Creteil, patients with multiple hallucinogenic episodes are thought to be at risk for cognitive decline even if their current cognition is normal; those with a single hallucinogenic episode are considered more likely to have a pharmacologic etiology and could potentially remain eligible for STN-DBS. Similarly, Michele York, PhD, an assistant professor of neurosurgery at Baylor College of Medicine in Houston, said that at her institution PD patients with drug-related hallucinations have had positive outcomes using STN-DBS, but that those in whom hallucinations cannot be linked to PD drug use are not candidates for the procedure.

DEPRESSION

The practice parameter recommendations for treatment of depression in patients with Parkinson disease are, if anything, even less definitive than those for treatment of psychoses—such that its sole recommendation in this category comes with the caveats that “although the highest level of evidence is for amitriptyline, it is not necessarily the first choice for treatment of depression associated with PD,” and that “absence of literature demonstrating clear efficacy of non-tricyclic antidepressants is not the same as absence of efficacy.”¹

The subcommittee's level C recommendation of amitriptyline was based on a 2002 study from Quito, Ecuador, in which 77 patients with PD and depression were randomized to receive either amitriptyline or fluoxetine daily for 12 months.³⁶ The researchers found that amitriptyline more effectively controlled the depressive symptoms than fluoxetine, but also reported that 15% of patients receiving amitriptyline dropped out of the study after experiencing adverse events; no similar attrition occurred in the fluoxetine group.

Study design flaws prevented the subcommittee from drawing definitive conclusions about the efficacy of other potential anti-depressive drugs associated with fewer anticholinergic side effects than amitriptyline. Spanish researchers found no significant difference in Beck Depression Inventory score improvement between nefazodone and fluoxetine, with the nefazodone group demonstrating significantly greater improvement in UPDRS scores,³⁷ but because of a lack of placebo control the subcommittee was unable to determine the anti-depressant efficacy of either drug. A 1980 study reported that patients receiving the tricyclic antidepressant nortriptyline experienced significantly greater improvement of depressive symptoms than patients receiving placebo,³⁸ but the subcommittee was unable to confirm this significance. A 1998 study comparing citalopram to placebo found no significant anti-depressive benefit,³⁹ nor did a 2003 study comparing sertraline to placebo,⁴⁰ but the subcommittee found that both SSRI studies lacked the statistical power to demonstrate clinically significance. And although Czech researchers found in 2003 that patients receiving pramipexole experienced significant improvement in Montgomery and Asberg Depression Rating Scale scores while those receiving pergolide did not,¹⁷ the subcommittee concluded that between-group differences in the severity of depression at baseline compromised the study's findings.

Since the end of the time period reviewed by the subcommittee, two additional published studies appear to support the anti-depressive efficacy of pramipexole. In May 2005, a multicenter European study led by German researchers reported significant improvements in depression scores in 174 patients who received pramipexole, compared to 180 patients who received placebo.³¹ An Italian study of 67 patients, published online in April prior to print publication in the Journal of Neurology, found that 60% of those who received open-label pramipexole achieved a 12-week score of 8 or higher on the Hamilton Depression Rating Scale, compared to 27.3% of those who received sertraline.⁴² And a prospective Italian study published in January suggests that the noradrenaline reuptake inhibitor reboxetine may also help improve depressive symptoms, with HAM-D scores improving from 16.76 to 2.42 after 4 months in 17 patients; mean UPDRS scores did not change significantly during that time.⁴³

In addition, patients receiving dopamine agonists either as monotherapy or in combination with levodopa demonstrated lower scores on the Hospital Anxiety and Depression Scale than those on levodopa monotherapy, in a study of 1351 patients presented in April at the annual meeting of the AAN.¹⁸

“Depression was the only variable influenced by pharmacologic treatment,” said Jaime Kulisevsky, MD, a neurologist at Sant Pau Hospital in Barcelona, who presented his group's findings at the AAN meeting.

The risk that anticholinergic side effects will exacerbate PD-related symptoms is a challenge of treating depression in any PD patient, as is Weintraub's anecdotal observation that many PD patients with depression do not respond to pharmacotherapy or would prefer not to take any additional medications.⁷ But where the Faustian dilemma recurs is when the potential benefits of STN-DBS for treatment of axial motor symptoms that do not respond to pharmacologic therapy must be weighed against accumulating evidence of depression and even suicide as adverse effects associated with the procedure.

Several studies published or presented between 2001 and 2003 reported that between 6% and 30% of patients develop depression following STN-DBS for Parkinson disease treatment.^8-11 At least one study ¹² indicated that a pre-procedural history of depression may be a risk factor for postoperative depression, and the challenge of accurately diagnosing depression in PD patients leaves open the possibility that more cases of postoperative symptoms actually reflect subclinical pre-existing disease. It is also possible, however, that depression is triggered or exacerbated by positioning of electrodes that deviates even slightly from optimal stimulation sites, as suggested by a pilot study from the University of Florida published in 2003.⁴⁴

The issue of suicide following STN-DBS therapy is even trickier, given the surprising fact that PD patients with depression in general are less likely to attempt suicide than depressed patients without PD, although depressed PD patients do have high rates of suicidal ideation.⁴⁵ However, in a multicenter retrospective study of more than 5000 patients, an international team of researchers led by Valerie Voon, MD, a staff psychiatrist at the University of Toronto and researcher at the National Institute of Neurological Disorders and Stroke in Bethesda, MD, found that postoperative depression was a significant predictor of both attempted and completed suicides.⁴⁶ In the 46 cases (0.88%) of postoperative attempted suicide, the researchers also found that a preoperative history of impulse control disorders or substance abuse, preoperative suicidal ideation or attempts, and postoperative apathy were predictive factors, with the patients who underwent STN-DBS immediately preceeding and immediately following the suicidal patient serving as controls. In the 22 cases (0.46%) of completed suicide, postoperative depression was the only risk factor identified. Although the percentage of postoperative levodopa decrease was not associated with suicide risk, Voon speculated that high levels of preoperative levodopa use could be related to impulse control disorders.

“Like any other life-altering surgery, there are complications that can occur,” said Voon, who presented the team's findings at the AAN meeting, and recommended that counseling be provided to patients and their families as a preventive measure.

Risk factors, of course, are not absolutes. In a series of 31 patients who underwent STN-DBS at Baylor College of Medicine,⁴⁷ York and colleagues reported 2 suicide attempts and 1 completion. The latter patient had no apparent risk factors, York said.

“He seemed like the ideal candidate for deep brain stimulation,” she said.

NO GUARANTEES

All told, it seems that despite increasing interest on the part of researchers and awareness on the part of physicians, the Faustian dilemma for clinicians treating Parkinson patients will have no easy answers any time soon. In the interim, clinicians may need to rely—perhaps more than they'd like to—on their best professional judgement in weighing the risks of neuropsychiatric complications against the potential benefits of antiparkinsonian therapies.

“When treating individual patients, the absence of certain risk factors does not guarantee immunity from development of a particular psychiatric disorder,” Lauterbach said. “Therefore, the best approach is to be aware of psychiatric complications for which a patient is at risk, and to carefully observe for these conditions as treatment is instituted and maintained. A history of a previous psychiatric disorder is an indication to observe for its recurrence, even if the condition has not been specifically related to the particular treatment modality, because the nonspecific stressor of PD itself may serve to encourage its relapse.”

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