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Several open-label studies suggest that atypical antipsychotic agents can improve psychotic symptoms in DLB (125,126). However, DLB sufferers seem to be particularly vulnerable to a specific type of adverse reaction to neuroleptic agents. Patients develop severe parkinsonism, impairment of consciousness, autonomic instability, and frequently experience falls and a marked drop in their level of cognitive performance and functioning (127,128). Furthermore, even in DLB patients who do not experience severe neuroleptic sensitivity, there is some evidence that neuronal loss in the caudate and putamen may be exacerbated by neuroleptic treatment (129). Given the major concerns regarding severe neuroleptic sensitivity reactions, neuroleptic agents cannot be considered to be the first-choice management approach for neuropsychiatric symptoms, but may possibly still have a role in severe and intractable cases with psychosis.

A number of case reports and case series indicate that cholinesterase inhibitors may improve not only the cognitive impairment, but also the psychiatric symptoms in approx 170% of DLB cases with good tolerability (with no exacerbation of parkinsonism in most reports). The first double-blind, placebo-controlled trial of cholinesterase inhibitor therapy for the treatment of DLB confirms these encouraging results (113). The total NPI score improved in 61% of patients on rivastigmine compared with 28% in the placebo group. Hallucinations and delusions, apathy, anxiety, and motor overactivity were the symptoms that improved most markedly. Rivastigmine was well tolerated with no increase in adverse events requiring withdrawal in comparison with the placebo group. Furthermore, there was no deterioration in parkinsonism in the treatment group. Given the potential hazards of neuroleptic treatment, most specialists would now recommend cholinesterase inhibitor therapy as a first-line treatment for neuropsychiatric symptoms in DLB patients. The evidence is still however preliminary, and further double-blind, placebo-controlled trials are probably needed before confident, evidence-based practice guidelines could be developed.

A variety of other psychotropic drugs are used in the short-term clinical management of DLB. Anxiety and insomnia are common symptoms that may respond well to benzodiazepine sedatives and antidepressant, and anticonvulsants may be useful in controlling behavioral and psychotic symptoms. Most of these observations are based upon clinical experience and anecdote, rather than evidence; and given the poor tolerability of DLB patients to psychotropic drugs, it is probably best to avoid all pharmacological interventions with psychotropic agents other than cholinesterase inhibitors, unless the clinical situation makes it imperative. Given the potential adverse response to neuroleptics, studies evaluating the potential value of nonpharmacological treatment approaches are also needed. Another key issue for future trials is the management of depression in these patients (see Future Research Issues), since no pharmacological or nonpharmacological studies have been published so far.

TREATMENT OF PSP, CBD, AND MSA

Few trials of neuropsychiatric symptoms have been reported in PSP. In a recent placebo-controlled trial, the cholinesterase inhibitor donepezil did not improve neuropsychiatric symptoms. A slight improvement in memory was noted, but because of worsening of motor symptoms, a worsening of ADL was found in patients receiving donepezil (116). Similarly, a small placebo-controlled trial with RS-86, a cholinergic agonist, did not improve cognition or mood in PSP patients with dementia (115). In a clinical survey, it was reported that some PSP patients responded to antidepressive drugs (77). In a chart review, 7 of 12 autopsy-diagnosed PSP patients responded to a dopaminergic drugs, and 1 of 3 to a tricyclic antidepressant. None of the patients responded markedly, however. The serotonergic agent trazodone, but not the neuroleptic drug thiotixine or carbamazepine, improved agitation in patients with PSP (130). Another case report suggested that electroconvulsive therapy (ECT) could improve depression without affecting motor symptoms in PSP (131). Similar findings have been reported in PD patients (132). Very few reports of the treatment of neuropsychiatric symptoms exist for patients with CBD and MSA. In a large clinical survey of CBD patients, antidepressive therapy was reported not to improve depression, whereas four of six patients exposed to neuroleptics showed clinical improvement (88). Further details of the treatments were not provided, however. In a patient with MSA, clozapine was reported to improve psychotic depression without aggravating neurological abnormalities (98). ECT was reported to be a safe and effective treatment for major depression in some patients with MSA (101,133), with long-term benefit in some (134).

In summary, although some placebo-controlled drug trials of neuropsychiatric symptoms in par-kinsonian disorders have been reported, there is limited evidence available to guide pharmacological treatment for patients with atypical parkinsonian disorders.

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