Drug treatment of psychiatric and behavioural symptoms

In common with other types of dementia, it is the psychiatric and behavioural symptoms which cause the greatest distress to patients and carers, and which eventually lead to requests for treatment and institutional care [36]. In Lewy body dementias such symptoms are frequent and contribute to greater impairment in quality of life and costs of care than for AD patients with equivalent cognitive impairments [37, 38]. In addition to the cognitive effects of ChE-Is described earlier, the same agents have also been reported to improve a range of neuropsychiatric symptoms in PD-D and DLB, particularly apathy, visual hallucinations, anxiety, sleep disturbances, and delusions [3]. It is possible that these behavioural effects are largely mediated via improvements in attention and cognitive processing. Since cognitive and neuropsychiatric symptoms often go hand in hand, the choice of a ChE-I as the first-line drug treatment is often directed at both domains.

Agitation and related behaviours are less likely to improve with ChE-Is and occasionally may even be aggravated. The mainstay of treatment for agitation, aggression, and psychotic symptoms in dementia has generally been with D2 receptor antagonists, but these drugs, particularly traditional neuroleptic agents, can provoke severe neuroleptic sensitivity reactions in up to 50% of DLB patients and 25% of PD-D patients, with a two- to three-fold increased mortality [2, 39-41], therefore they are contraindicated in this patient population. These reactions are generally acute or subacute, becoming evident within the first few doses or after increase from a previously tolerated dose. When acute deterioration occurs in a confused elderly patient following neuroleptic administration, Lewy body disease should always be considered as part of the differential diagnosis. Following initial positive case reports of the use of newer atypical antipsychotics in DLB, further case studies indicate that neuroleptic sensitivity does occur with both risperidone and olanzapine, especially as the dose is increased [42, 43]. Quetiapine did not appear to significantly worsen motor symptoms in a recent, small placebo-controlled trial of 36 patients with DLB [44], but was not associated with significant improvement in psychiatric or cognitive outcome measures. Clozapine may also be useful in treating PD psychosis, but its antimuscarinic properties may increase confusion in patients with dementia [45]. The frequent occurrence of electroencephalogram abnormalities with transient temporal slow waves has prompted the use of car- bamazepine and sodium valproate as agents to treat behavioural disturbance, but no systematic reports of efficacy or side effects are available. The 5-HT3 antagonist ondansetron was reported as having antipsychotic effects in PD patients with hallucinations, but this has not been independently replicated and the high doses required make the cost prohibitive for routine practice [46]. There are sporadic reports of the traditional Japanese medicine yokukansan being effective and well-tolerated in the treatment of ChE-I-resistant visual hallucinations and neuropsychiatric symptoms in patients with DLB, but this needs confirmation [47].

Although disorders of affect and depressive features are among the most frequent behavioural symptoms in PD and PD-D, surprisingly there have been no randomized, controlled studies of antidepressants in the PD-D population. A meta-analysis of all studies in PD patients with depression revealed large effect sizes, both under active treatment and placebo. There were, however, no statistically significant differences between them; increasing age and major depression predicted better response [48]. In another systematic review, amitriptyline was reported to be the only compound with evidence of efficacy in PD depression [49]. In the past few years there have been several placebo-controlled randomized trials in PD patients with depression, although none were specifically in PD-D patients. In one study desipramine and citalopram were both significantly better than placebo [50], in another nortriptyline was significantly better than placebo whereas paroxetine was not [51]. In contrast, both paroxetine and venlafaxine were significantly better than placebo in a larger randomized trial [52]. The dopamine agonist pramipexole was shown to be significantly better than placebo in a large randomized placebo-controlled trial in patients without dementia but with depressive symptoms [53]; agonists, however, can worsen psychosis and cognition in PD-D patients. It should be remembered that all randomized controlled trials were conducted in patients without dementia. There is a hint that tricyclics such as amitriptyline and nortriptyline may have larger effect sizes, but they should be avoided in PD-D patients because of their anticholinergic effects and hence the potential to worsen cognition. Although an evidence base is lacking, empirically selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and noradrenaline reuptake inhibitors (SNRIs) should be preferred in these patients. Elevated 5-HT1A receptor density has been reported in the temporal cortex of PD-D and DLB patients with a history of depression, suggesting that a 5-HT1A receptor antagonist adjuvant may improve treatment of depression in this group [54].

Disturbances of the sleep-wake cycle, including excessive daytime sleepiness and rapid eye movement (REM) sleep behaviour disorder (RBD), frequently occur in patients with PD-D or DLB [55]. Disturbed sleep with thrashing limb movements, vocalizations, and vivid dreams may precede Lewy body disease as an early manifestation, and may persist, sometimes in attenuated form. Treatment of RBD lacks a double-blind, placebo-controlled, evidence base. Clonazepam has been reported as effective and well tolerated [56] in suppressing the motor features, but does not restore REM sleep atonia [57]. Melatonin has been reported to be beneficial, with control of symptoms or significant improvement being noted in 10 of 14 patients who had failed to respond to clonazepam or were unable to tolerate therapeutic doses [58]. Memantine has also been reported to reduce physical activity in DLB and PD-D during sleep, but no significant change was observed in the severity of excessive daytime sleepiness which is also a frequent problem [59]. In studies performed in PD patients without dementia, modafinil, an agent that promotes wakefulness through undetermined mechanisms, was found to be significantly better than placebo in two small randomized, placebo-controlled studies [60, 61], but its use in DLB may be associated with agitation and psychosis [62]. Armodafinil, the racemic form of modafinil, was reported as showing mild to marked clinical improvement in 90% of participants in a small open-label trial, with moderate to marked improvement seen in half of these. Significant improvement over baseline was reported in the ability to maintain wakefulness and also in apathy, with some improvement in visual hallucinations, delusions, and anxiety. Treatment was well tolerated, and this appears to be a promising avenue for further evaluation [63].

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