A controlled trial of antidepressants in patients with Parkinson Disease and depression

Department of Psychiatry, Robert Wood Johnson Medical School, UMDNJ-University Behavioral Health Care, Piscataway, NJ 08854, USA.
Neurology (Impact Factor: 8.29). 12/2008; 72(10):886-92. DOI: 10.1212/01.wnl.0000336340.89821.b3
Source: PubMed


Parkinson disease (PD) is a common neurodegenerative disease affecting up to 1 million individuals in the United States. Depression affects up to 50% of these patients and is associated with a variety of poor outcomes for patients and their families. Despite this, there are few evidence-based data to guide clinical care.
An NIH-funded, randomized, controlled trial of paroxetine CR, nortriptyline, and placebo in 52 patients with PD and depression. The primary outcomes were the change in the Hamilton Depression Rating Scale (HAM-D) and the percentage of depression responders at 8 weeks.
Nortriptyline was superior to placebo for the change in HAM-D (p < 0.002); paroxetine CR was not. There was a trend for superiority of nortriptyline over paroxetine CR at 8 weeks (p < 0.079). Response rates favored nortriptyline (p = 0.024): nortriptyline 53%, paroxetine CR 11%, placebo 24%. In planned contrasts of response rates, nortriptyline was superior to paroxetine CR (p = 0.034). Nortriptyline was also superior to placebo in many of the secondary outcomes, including sleep, anxiety, and social functioning, while paroxetine CR was not. Both active drug treatments were well tolerated.
Though relatively modest in size, this is the largest placebo-controlled trial done to date in patients with Parkinson disease (PD) and depression. Nortriptyline was efficacious in the treatment of depression and paroxetine CR was not. When compared directly, nortriptyline produced significantly more responders than did paroxetine CR. The trial suggests that depression in patients with PD is responsive to treatment and raises questions about the relative efficacy of dual reuptake inhibitors and selective serotonin reuptake inhibitors.

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    • "Tricyclic antidepressants acting on noradrenaline reuptake, such as desipramine and reboxetine, as well as citalopram , a selective serotonin reuptake inhibitor, reduce depression associated to PD (Lemke, 2002; Devos et al., 2008). Nortriptyline, which blocks noradrenaline and serotonin reuptake, is also able to reduce depression in PD patients (Menza et al., 2009). However, mood disorders in PD are still considered difficult to treat, possibly due to the low dosage of appropriate medications normally employed to avoid worsening of motor symptoms (Weintraub et al., 2003). "
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    ABSTRACT: Non-motor symptoms, including psychiatric disorders, are increasingly recognized as a major challenge in the treatment of Parkinson's disease (PD). These ailments, which often appear in the early stage of the disease, affect a large number of patients and are only partly resolved by conventional antiparkinsonian medications, such as L-DOPA. Here, we investigated non-motor symptoms of PD in a mouse model based on bilateral injection of the toxin 6-hydroxydopamine (6-OHDA) in the dorsal striatum. This model presented only subtle gait modifications, which did not affect horizontal motor activity in the open-field test. Bilateral 6-OHDA lesion also impaired olfactory discrimination, in line with the anosmia typically observed in early stage parkinsonism. The effect of 6-OHDA was then examined for mood-related dysfunctions. Lesioned mice showed increased immobility in the forced swim test and tail suspension test, two behavioral paradigms of depression. Moreover, the lesion exerted anxiogenic effects, as shown by reduced time spent in the open arms, in the elevated plus maze test, and by increased thigmotaxis in the open-field test. L-DOPA did not modify depressive- and anxiety-like behaviors, which were instead counteracted by the dopamine D2/D3 receptor agonist, pramipexole. Reboxetine, a noradrenaline reuptake inhibitor, was also able to revert the depressive and anxiogenic effects produced by the lesion with 6-OHDA. Interestingly, pre-treatment with desipramine prior to injection of 6-OHDA, which is commonly used to preserve noradrenaline neurons, did not modify the effect of the lesion on depressive- and anxiety-like behaviors. Thus, in the present model, mood-related conditions are independent of the reduction of noradrenaline caused by 6-OHDA. Based on these findings we propose that the anti-depressive and anxiolytic action of reboxetine is mediated by promoting dopamine transmission through blockade of dopamine uptake from residual noradrenergic terminals.
    Frontiers in Behavioral Neuroscience 08/2014; 8:290. DOI:10.3389/fnbeh.2014.00290 · 3.27 Impact Factor
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    • "A forest plot of effect sizes and 95% confidence intervals for all interventions reporting the secondary effect of treatment on anxiety, as well as the pooled effect for antidepressants, SSRIs and TCAs appears in Figure 3. Apart from paroxetine which showed no significant effect on anxiety, all interventions resulted in large and statistically significant reductions in anxiety with effect sizes ranging from.93 to 1.98. A pooled effect size for antidepressants was computed by pooling data from the Devos et al. [17] and Menza et al. [19] trials. The pooled effect size for antidepressants on anxiety in PD was large (d = 1.13) but non-significant (95% CI = –.67 to 2.94). "
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    ABSTRACT: Psychopharmacotherapy currently constitutes the first-line treatment for depression and anxiety in Parkinson's disease (PD) however the efficacy of antidepressant treatments in PD is unclear. Several alternative treatments have been suggested as potentially more viable alternatives including dopamine agonists, repetitive transcranial magnetic stimulation, and cognitive behavioural therapy (CBT). A meta-analysis of randomised placebo-controlled trials for depression and/or anxiety in PD was conducted to systematically examine the efficacy of current treatments for depression and anxiety in PD. Nine trials were included. There was only sufficient data to calculate a pooled effect for antidepressant therapies. The pooled effect of antidepressants for depression in PD was moderate but non-significant (d = .71, 95% CI = -1.33 to 3.08). The secondary effect of antidepressants on anxiety in PD was large but also non-significant (d = 1.13, 95% CI = -.67 to 2.94). Two single-trials of non-pharmacological treatments for depression in PD resulted in significant large effects; Omega-3 supplementation (d = .92, 95% CI = .15 to 1.69) and CBT (d = 1.57, 95% CI = 1.06 to 2.07), and warrant further exploration. There remains a lack of controlled trials for both pharmacological and non-pharmacological treatments for depression and anxiety in PD which limits the conclusions which can be drawn. While the pooled effects of antidepressant therapies in PD were non-significant, the moderate to large magnitude of each pooled effect is promising. Non-pharmacological approaches show potential for depression in PD however more research is required.
    PLoS ONE 11/2013; 8(11):e79510. DOI:10.1371/journal.pone.0079510 · 3.23 Impact Factor
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    • "The comparison between SSRIs and TCAs didn't show statistical difference [4]. However, another study by Menza [5] suggested that the SSRI paroxetine CR was not superior to placebo in patients with PD and depression and might be inferior to nortriptyline. A recent review [6] by Klaus Seppi et al. considered that pramipexole was efficacious for the treatment of depressive symptoms in PD, whereas there was insufficient evidence regarding to pergolide. "
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    ABSTRACT: Depression is a common non-motor symptom in patients with Parkinson's disease (PD). There are many kinds of antidepressants being used, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and Dopamine agonists which are suggested as alternative antidepressants for the treatment of depression in PD. Which one should we choose first? Literatures have shown inconsistent results. We conducted a network meta-analysis of randomized controlled trials to compare the efficacy and acceptability of therapeutic methods for the treatment of depression in Parkinson's disease. We used the odds ratios (OR) as effect size firstly and the results indicated no statistical significance between each compared intervention. Then we used the logarithm of the individual odds ratios as effect size. With efficacy of TCAs as the standard of comparison, the degree of incoherence (a measure of how closely the entire network fits together) was small (ω = 4.824827e-05). The logor were: SSRIs -0.69 (95% CI -1.28- -0.10); Pramipexole -0.73 (-1.71- -0.26); Pergolide -1.97 (-3.67- 0.27); SNRIs -0.86 (-1.86- 0.15); Placebo -1.24 (-1.99- -0.50). With Placebo as the standard of comparison, the logor were: TCAs 1.24 (0.50- 1.99); SSRIs 0.55 (-0.03- 1.13); Pramipexole 0.51 (-0.12- 1.15); Pergolide -0.73 (-2.25- 0.80); SNRIs 0.38 (-0.42- 1.19); TCAs, pramipexole, pergolide and SNRIs showed better profile of acceptability, leading to significant fewer discontinuations than that of SSRIs. There is insufficient evidence to support antidepressant efficacy for SSRIs, pramipexole, pergolide and SNRIs. TCAs might be the best choice when starting antidepressant treatment in patients of Parkinson's disease because it has the most favorable balance between benefits and acceptability, followed by pramipexole and SNRIs, SSRIs might be the last choice.
    PLoS ONE 10/2013; 8(10):e76651. DOI:10.1371/journal.pone.0076651 · 3.23 Impact Factor
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