>Don't the apparently clear positive results today in PDP at least increase the odds of success in AD and schizophrenia?>
Somewhat. I give the AD trial for psychosis with Pimivanserin a less than 50% chance for stat sig results, but I must confess I do not recall the ratings instruments for the AD trial. (There are many issues to consider here, and I give some more color on this below.)
Why less than 50%? This is CNS and things that are seemingly similar are not always so. Why? Different CNS circuits involved and different transmitter systems involved in onset and progression. Animal models can be very here but there are limitations in the animal models. And the human situations are not equivalent to the models, though the PD models of >99% striatonigral dopamine secreting neuronal loss are quite similar to the human situation of PD. Recall that Pimavanserin is a serotonin 5HT-2a receptor inverse agonist, and that dopamine system alterations via 6-hydroxydopamine lesions of the substantia nigra result in alterations in the 5HT-2a receptor. Pimavanserin has shown activity against aspects of psychosis in both a PD model and in an A beta peptide induced model of AD - see pub med for Acadia publications here, or the ACAD website for citations.
Nevertheless, there are many complications here as much of the psychosis in PD is drug-induced, and not so for the AD patient. These facts may not be so meaningful you might say, but I would not say that. But the drug (Pima) may have different degrees of activity in both - more so in PD in my view. Further the ratings instruments for the 2 diseases are not equally sensitive on the psychosis endpoints - more so for PD. Note also the incidences for psychosis are much different for the 2 diseases, much greater for the PD patient. Finally, psychiatrists use antipsychotics and anti-agitation drugs off label quite a bit for AD patients.
Psychosis is a complex area of research, both in experimental animal models and in humans. Not all psychoses are created equal. PDP seems to be more gradual in onset that ADP. I personally would go after Lewy Body psychosis before ADP because there is more suggestion that central dopamine systems are involved. Here is an excerpt on the differences in psychosis in PD patients compared to Lewy Body patients (the precise neural circuitry is not well understood in the latter, as in somewhat similarly diseased AD patients):
ajp.psychiatryonline.org
Presentation and Management of Psychosis in Parkinson’s Disease and Dementia With Lewy Bodies
Treatment of PD Psychosis
Epidemiology | Correlates and Risk Factors | Presentation | Etiology and Pathophysiology | Assessment | Treatment of PD Psychosis | Treatment of DLB Psychosis | Safety and Tolerability | Summary and Recommendations | References
"... In conjunction with the steps outlined above, psychopharmacological treatment is initiated for persistent and problematic psychosis. Conventional antipsychotics are not recommended for use in patients with PD, as they have been reported to significantly worsen the motor aspects of parkinsonism (13). All randomized placebo-controlled studies of treatment for psychosis and related psychiatric disturbance in PD and DLB have tested either antipsychotics or cholinesterase inhibitors ( Table 1).
In the three adequately designed placebo-controlled studies of low-dose clozapine for the treatment of PD psychosis reported to date, clozapine was found to be significantly better than placebo in reducing positive symptoms of psychosis, with no worsening in parkinsonism or global cognition on average (27, 28, 33). Two reports on results of three placebo-controlled studies of olanzapine indicated no between-groups differences in efficacy, and olanzapine was associated with significant worsening of parkinsonism in all three studies, with a higher dropout rate in one study (29, 30). Finally, there have been two placebo-controlled trials of quetiapine, which anecdotally is the first-line treatment for psychosis in PD. In the first study, no significant differences between quetiapine (flexible dosage up to 200 mg/day) and placebo were reported for any efficacy measures, and no worsening of parkinsonism was found with quetiapine treatment (33). In the other study, quetiapine (mean dosage of 119 mg/day) was not efficacious for the treatment of PD psychosis, and only 55% of patients completed the study (34).
There have also been several antipsychotic comparator studies of treatment for PD psychosis, all involving clozapine. In a small randomized active comparator study of risperidone versus clozapine, only the risperidone group demonstrated improvement on the Brief Psychiatric Rating Scale (BPRS) psychosis cluster score, but the between-groups differences were not significant; neither group demonstrated a change in the Unified Parkinson’s Disease Rating Scale motor score (35). In a randomized, double-blind comparison of olanzapine and clozapine, the study was terminated early because of exacerbated parkinsonism in olanzapine-treated patients (36). Finally, in a randomized, single-blind active comparator study of quetiapine versus clozapine, both groups experienced significant improvement in total BPRS score with treatment, with no between-groups difference, and neither group had a worsening in Unified Parkinson’s Disease Rating Scale motor score (37). Summarizing the literature on antipsychotics in PD, a recent structured review and meta-analysis concluded that “only clozapine can be fully recommended for the treatment of drug-induced psychosis in PD” (38).
Aripiprazole, an atypical antipsychotic with partial agonism at D2 receptors, held promise as an antipsychotic in PD when it was first introduced, but two small open-label studies at varying dosages reported negative findings overall, with a significant percentage of patients discontinuing treatment because of worsening parkinsonism or lack of improvement in psychosis (39, 40). In a small case series of ziprasidone at a low dosage (20–40 mg/day) for the treatment of PD psychosis, 83% of the patients completed 12 weeks of treatment, with a significant overall improvement in total Neuropsychiatric Inventory score and no change in the Unified Parkinson’s Disease Rating Scale motor score (41).
There is some evidence that cholinesterase inhibitors may have antipsychotic properties in PD ( Table 2). Several small open-label studies have found donepezil and rivastigmine to be beneficial for PD psychosis in the context of dementia. Three placebo-controlled studies of cholinesterase inhibitors for the treatment of PD with dementia did not demonstrate superiority for donepezil relative to placebo for psychiatric symptoms, including psychosis; however, all studies were small, were designed to evaluate cognitive outcomes, and enrolled only participants with limited psychiatric comorbidity (43, 44, 46). A large placebo-controlled study of rivastigmine for PD with dementia found that the rivastigmine group had a significantly greater decrease in neuropsychiatric symptoms than the control group and were less likely to report hallucinations as an adverse event (45). In a secondary analysis, the greatest benefit from treatment with rivastigmine was found to occur in patients who had visual hallucinations at baseline (47). There are also case reports suggesting that antidepressants may have a role in the treatment of psychosis in PD."
Treatment of DLB Psychosis
Epidemiology | Correlates and Risk Factors | Presentation | Etiology and Pathophysiology | Assessment | Treatment of PD Psychosis | Treatment of DLB Psychosis | Safety and Tolerability | Summary and Recommendations | References
Only one prospective randomized study for the treatment of neuropsychiatric symptoms in DLB has been reported to date (42) (see Table 2). Rivastigmine led to significant improvement in most analyses on a composite neuropsychiatric score that included delusions, hallucinations, depression, and apathy, although it was not clear whether significant between-groups differences were seen for either delusions or hallucinations alone. In addition, the presence of visual hallucinations was found to predict improvement in attention (48). Cholinesterase inhibitors are the recommended first-line treatment for DLB because of their benefit for cognitive symptoms (49) and relative lack of toxicity compared with antipsychotic medications. In a small retrospective case series of memantine for DLB, the authors concluded that this agent can be used safely in this population, but approximately one-third of patients experienced a worsening in psychiatric or cognitive status with treatment (50).
In a placebo-controlled study of the treatment of psychosis in Alzheimer’s disease with olanzapine, a post hoc analysis of a subgroup of patients who were retrospectively diagnosed with DLB showed that olanzapine led to a decrease in positive symptoms of psychosis without worsening either parkinsonism or cognition (31) (see Table 1). A small open-label study of quetiapine for psychosis and agitation in DLB found that approximately half of patients treated with 25–75 mg/day of quetiapine experienced a clinically significant reduction in these symptoms, but several patients had to discontinue treatment because of somnolence or orthostatic hypotension (51). |
