Atypical Antipsychotics

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Atypical antipsychotics are typically used to treat psychosis in PD. Table 1 provides a summary of atypical antipsychotic studies in PD. The United States Food and Drug Administration (FDA) recently asked all atypical antipsychotic manufacturers to add a boxed warning to their product labels, saying that atypical antipsychotics, when used in elderly patients with dementia, were associated with a higher risk of mortality (54). However, since the deaths were primarily due to cardiovascular or infectious causes, it is unclear how the atypical antipsychotics cause increased mortality. Since psychosis can be difficult to treat in PD, it is likely that these agents will continue to be utilized until a direct cause and effect relationship is uncovered.

Clozapine

Clozapine was the first atypical antipsychotic approved by the FDA, and is the only atypical antipsychotic that has been demonstrated to have better efficacy than typical

Agent

Design

Number of patients

Dosage

Number of psychosis improved

Number of PD worsened

Clozapine

Wolters et al. (58)

Double-blind

6

75-250 mg/d

3

3

Parkinson Study

Group (56)

Double-blind

60

24.7 mg/d

Improved mean BPRS

0

Pollak et al. (57)

Double-blind with

60

36 mg/d

Improved mean CGIS, positive

open- label

subscore of PANSS

0

follow up

Risperidone

Meco et al. (68)

Open-label

6

0.67 mg/d

6

0

Fordet al. (71)

Open-label

6

1.5 mg/d

6

6

Rich et al. (72)

Open-label

6

0.5—4 mg/d

4

5

Workman et al. (67)

Open-label

9

1.9 mg/d

9

0

Meco et al. (73)

Open-label

10

0.73 mg/d

9

3

Leopold (74)

Open-label

39

1.1 mg/d

33

6

Mohret al. (75)

Open-label

17

1.1 mg/d

16

1

Olanzapine

US Olanzapine

Double-blind

41

4.2 mg/d

Improved total BPRS, NPI, and

Worsening of total and motor

trial (82)

CGIS psychosis scores

UPDRS scores

European Olanzapine

Double-blind

49

4.1 mg/d

Improved total BPRS, NPI, and

Worsening of total and motor

trial (82)

CGIS psychosis scores

UPDRS scores

Ondo et al. (81) scores

Double-blind

16

4.6 mg/d

No significant improvement overall

Worsened UPDRS motor

Quetiapine

Ondo et al. (88)

Double-blind

21

75-200 mg/d

No significant improvement in

No significant worsening

BPRS scores

of UPDRS scores

Rabey et al. (89)

Double-blind

30

119.2 mg/d

No difference compared to

No difference compared

placebo

to placebo

Reddy et al. (85)

Retrospective

43

54 mg/d

32

5

Fernandez et al. (86)

Retrospective

103

60.8 mg/d

84

13

Aripiprazole

Fernandez et al. (95)

Open-label

8

12.8 mg/d

4

3

Friedman et al. (96)

Open-label

14

1-5 mg/d

6

5

Abbreviations-. BPRS, Brief Psychosis Rating Scale; CGIS, Clinical Global Impression of Severity; NPI, Neuropsychiatrie Inventory; PANSS, Positive and Negative Syndrome Scale; PD, Parkinson's disease; UPDRS, Unified Parkinson's Disease Rating Scale.

Abbreviations-. BPRS, Brief Psychosis Rating Scale; CGIS, Clinical Global Impression of Severity; NPI, Neuropsychiatrie Inventory; PANSS, Positive and Negative Syndrome Scale; PD, Parkinson's disease; UPDRS, Unified Parkinson's Disease Rating Scale.

neuroleptics (55). Double-blind placebo-controlled and open-label studies with clozapine have shown that the drug effectively treats psychosis in PD without worsening motor function (53,56,57). The first double-blind, placebo-controlled trial of clozapine in PD resulted in the only negative study (58). It was a small study of six patients at a single site. Three patients completed the study and three had worsened parkinsonism. However, the authors titrated clozapine using a schizophrenia titration schedule and went as high as 250mg/d. This resulted in subjects complaining of severe sedation, which may have partly manifested as worsened parkinsonism. We now know that doses as small as 6.25 mg daily can result in improvement of psychosis in PD patients.

Two randomized, double-blind, placebo-controlled trials of low-dose clozap-ine have been published (56,59). One trial was conducted in the United States and one in France. In the U.S. trial, clozapine, at a mean dose of 25mg/d, resulted in a significant benefit on four measures of psychosis. Motor function did not decline, and tremor improved significantly. Only one subject suffered a decline in white blood cell (WBC) count requiring termination, which was reversed within one week after stopping clozapine. The most commonly used dose was 6.25 mg/d. The French study reported similar results, with patients taking a mean dose of 35 mg/d.

In terms of long-term efficacy and safety, a retrospective analysis of 39 parkin-sonian patients on a mean dose of 47mg/d of clozapine for 60 months showed that 85% had continued response to the medication, whereas 13% had complete resolution of psychosis (60). A second study reported a five-year follow-up of 32 patients with PD and psychosis, 14 of whom had dementia (61). Nineteen of these patients were still taking clozapine at a mean dose of 20 mg/d. Nine subjects had stopped clozapine because of improvement in their psychosis, but three patients discontinued the drug due to somnolence.

Unfortunately, with clozapine, there is concern about agranulocytosis. Therefore, weekly WBC monitoring for six months, biweekly monitoring for the next six months, and monthly monitoring thereafter is mandated. This complication is not dose-related, so monitoring must be performed in all patients on clozapine. Although agranulocytosis had been thought to occur in 1% to 1.5% of patients, the actual incidence of agranulocytosis was only 0.38% in a recent analysis of over 99,000 U.S. patients with schizophrenia (62). Sedation, orthostatic hypotension, and sialorrhea are other common side effects of clozapine (57), but anticholinergic side effects have not been a major problem in PD (56). More recently, the use of atypical antipsychotics has been associated with a "metabolic syndrome" (insulin resistance, weight gain, dyslipidemia, and abnormal glucose metabolism) in schizophrenic patients (63). This has not been shown to occur in PD patients. The prevalence of diabetes in 44 parkinsonian subjects was similar to that of an age-matched group in the general population (60). This may be because subjects in this study were on a smaller dose of clozapine (50.6 mg/d) when compared to doses used in schizophrenic patients (300-900 mg/d). In summary, low dose clozapine is safe and effective for psychosis in PD patients. However, due to stringent monitoring, the search for a more practical and "low-maintenance" treatment for psychosis in PD remains an important goal.

Risperidone

Risperidone is chemically distinct from clozapine and was found to behave more like "typical" neuroleptics, with a dose-dependent incidence of extrapyramidal side effects (64,65). In PD, all but one report of risperidone were open-label (Table 1).

Although risperidone was effective for psychosis in general, some reports describe the complete absence of motor side effects (67-69), whereas others report severe motor worsening in each patient who took the drug (70,71). The few studies that reported no worsening of parkinsonism followed small numbers of patients for a short period of time. Five open-label studies of risperidone reported 78 PD patients on doses ranging from 0.5 to 4.0 mg/d, with 21 having worsening of motor features (71-75), although in the largest open-label study (39 patients), five of the six patients that worsened were thought to have DLB, rather than PD (74).

In the only double-blind study of risperidone (66), the efficacy and safety of risperidone and clozapine were compared. Ten subjects with PD psychosis were enrolled. The mean motor Unified Parkinson's Disease Rating Scale (UPDRS) score worsened in the risperidone group and improved in the clozapine group, though this difference did not reach statistical significance. On the contrary, risperidone improved psychosis and clozapine did not.

It is unclear why the results of risperidone studies in PD are so mixed, but multiple factors may be responsible. Most of the studies were open-label and differ in terms of speed of medication titration and duration of the observations. However, given the results in the PD population thus far, it is unlikely that a double-blind placebo-controlled trial will be performed, and many movement disorder specialists are reluctant to place patients on this agent.

Olanzapine

Olanzapine has a chemical structure similar to clozapine. It offered more promise than risperidone, because it induced catalepsy at higher doses than would be used in humans (76) and did not cause significant prolactin secretion, a feature seen with risperidone (77). The first open-label study of olanzapine in PD showed that it was effective for drug-induced psychosis in 15 nondemented patients, at a mean dose of 6.5 mg/d, without worsening motor function (78). However, all subsequent open-label studies of olanzapine in PD showed that approximately 40% of subjects had motor decline (79). Four double-blind trials of olanzapine have been published, three of which were placebo-controlled and one which compared olanzapine to clozapine (80-82). The clozapine trial was prematurely stopped because six of seven olanzap-ine treated subjects had significant motor decline (80). All three of the placebo-controlled trials reported that olanzapine had no effect on psychosis in PD and exacerbated parkinsonism (81, 82). In addition, sedation and weight gain were common undesirable side effects. An evidence-based review of the treatment of psychosis in PD concluded that "there is insufficient evidence to demonstrate efficacy of olanzapine" and "olanzapine carries an unacceptable risk of motor deterioration" at low doses (83).

Quetiapine

Of all the atypical antipsychotics, quetiapine has the closest structural resemblance to clozapine. It has a strong affinity for the serotonin 5-HT2 receptor and moderate affinity for the dopamine D2 receptor (84). It also has low affinity for the muscarinic receptor, and thus anticholinergic effects are not seen. Agranulocytosis has not been reported with quetiapine.

There have been multiple open-label studies of quetiapine for drug-induced psychosis in PD—the two largest reports have been retrospective analyses. Reddy et al. (85) found that 35 of 43 PD patients treated with quetiapine had improved psychosis. Five patients (13%), all of whom were demented, experienced mild worsening of motor symptoms but not significant enough to discontinue treatment. Fernandez et al. (86) reported 106 parkinsonian patients treated with quetiapine. Seventy-eight out of 106 (74%) remained on quetiapine for a mean duration of 15 months at an average dose of 60mg/d. Eighty-seven (82%) patients had partial or complete resolution of their psychosis, whereas 19 (18%) patients had no improvement. Motor decline was noted in 34 (32%) patients, but rarely warranted quetiapine discontinuation. Demented subjects had a 12-fold increased risk of nonresponse.

A double-blind, randomized, comparison trial of 40 PD patients placed on either quetiapine or clozapine found that both medications improved psychosis (87). There was no difference between the two groups in any parameters, either behav-iorally or motorically, and the investigators concluded that both medications were equally efficacious. However, in two double-blind, placebo-controlled trials, quetiapine was not found to be efficacious for PD psychosis (88,89). In one trial (88), 31 subjects with PD psychosis were randomized in a 2:1 double-blind fashion to quetiapine or placebo. The final dose of quetiapine ranged from 75 to 200mg/d, but the trial may not have been adequately powered to detect an effect. The second doubleblind, placebo-controlled trial randomized 30 patients to quetiapine (mean dose 119mg/d) and 28 patients to placebo (89). Fifteen patients in the quetiapine group discontinued the medication, 10 of them because of lack of efficacy. The authors postulated that the large dropout rate might have influenced their results. The results of these two trials are surprising, given that the available open-label studies of over 400 patients suggest that quetiapine appears to be well tolerated and effective. Future double-blind studies with larger numbers of subjects are needed.

Ziprasidone

Ziprasidone has a much higher affinity for serotonin 5-HT2 than dopamine D2 receptors and other atypical agents (90). Ziprasidone prolongs the QT interval, which has limited its use. However, there have been no cases of ziprasidone causing torsades de pointes (91). There have been only two case series reported on ziprasi-done in PD. The first was a small open-label, 12-week trial in 12 PD patients (mean age 72.1 years) with psychosis (92). Mean doses of ziprasidone were 24 mg at one month and 32 mg at 12 weeks, with an improvement in psychosis of 58% after one month and 72% at 12 weeks. Although two patients had a slight worsening of motor symptoms, the UPDRS motor scores did not significantly worsen over the course of the trial. Two patients had to withdraw from the study, one because of sedation and the other due to gait deterioration. The second open-label report investigated an intramuscular preparation of ziprasidone for the emergency treatment of psychosis in PD (93). Five patients were given gluteal intramuscular injections of either 10 or 20 mg of ziprasidone. The mean BPRS score before injection was 72 and improved to 48 two hours after injection. During the 24 hours following the injections, there was no worsening of parkinsonian symptoms. On the basis of these studies, it appears that ziprasidone may be helpful for psychotic symptoms in PD without worsening parkinsonism. However, on the basis of a review of the available data on ziprasidone in schizophrenia, it was concluded that its extrapyramidal symptom profile is "the same as olanzapine but not quite as good as quetiapine or clozapine" (94).

Aripiprazole

Aripiprazole differs from the other agents in that it is a partial agonist at the D2 and 5HT1 receptors and an antagonist at the 5HT2a receptors. Aripiprazole also has a high 5HT/D2 affinity ratio, which theoretically makes it less likely to cause extrapyramidal symptoms. The data on aripiprazole in PD are scarce. An initial open-label study showed that aripiprazole improved psychosis completely in two out of eight subjects with PD, whereas the other six subjects discontinued the medication: two due to lack of efficacy, two due to motor worsening, one due to lack of motor improvement, and one due to intolerable restlessness and confusion (95). Another study of 14 PD subjects with drug-induced psychosis showed that aripiprazole (dose range 1-5mg/d) improved psychosis in six patients, worsened psychosis in four, and caused no significant change in four (96). Eight subjects in this study withdrew: three because of worsened parkinsonism, two because of increased psychosis, two due to both worsened parkinsonism and psychosis, and one because of lack of efficacy. Although these studies were open-label and preliminary, they suggest that aripiprazole has a variable effect on psychotic symptoms, causes a high dropout rate due to adverse effects, and therefore should be used with caution in the PD population.

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