The Parkinson's-Reversing Breakthrough

What is Parkinsons Disease

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Patients with PD and untreated depression experience reduced quality of life compared with those who are depressed and taking antidepressant medications (62). Additionally, depression in PD patients often persists or worsens longitudinally, and untreated minor depression commonly progresses to major depression. Therefore, even mild depressive disturbances should be considered clinically significant and should warrant monitoring if not definitive treatment. The efficacy and safety of various antidepressants in the management of depression in patients with PD has been addressed in numerous uncontrolled studies (42,56,121-138) and a few controlled studies (139-150).

Pharmacologic Tricyclic antidepressants

The TCAs inhibit synaptosomal reuptake of dopamine, norepinephrine and, to a lesser extent, 5-HT. The TCAs also possess antimuscarinic and antihistaminic properties. Amitriptyline (139,144,147), desipramine (149), imipramine (150), and nortriptyline (148) have demonstrated antidepressive effects in randomized, controlled trials involving parkinsonian patients. Although these studies have methodologic limitations, all study agents were found to be effective. In two studies conducted in the prelevodopa era, desipramine and imipramine improved parkinsonian motor symptoms, as well as symptoms of anxiety and depression (149,150). Uncontrolled studies have reported favorably on the efficacy of imipramine in treating PD depression (137,138). There are no published data on doxepin for the management of depression in PD.

The tertiary amine TCAs (e.g., amitriptyline and imipramine) are associated with clinically significant central and peripheral side effects (e.g., antimuscarinic effects, confusion, hallucinations, hypotension, sedation, sexual dysfunction, and weight gain) that are often undesirable and/or intolerable for patients (Table 1), especially the elderly. However, in a subset of patients, such as those with bladder hyperactivity or drooling, the antimuscarinic activity of TCAs may be of added benefit. Sedating TCAs (e.g., amitriptyline) are also often selected for patients with insomnia (49). The secondary amine TCAs (e.g., desipramine and nortriptyline) are associated with a milder degree of side effects and are preferable if potent anti-muscarinic effects are not desired. Lastly, the TCAs rarely have been associated with treatment-emergent extrapyramidal symptoms (151,152).

Selective serotonin reuptake inhibitors

The SSRIs inhibit the synaptosomal reuptake of 5-HT and are generally preferred over the TCAs because of better overall tolerability (11) (Table 1). For the management of depression in patients with PD, all currently available SSRIs have been studied; albeit the numbers of patients in the trials have been small. Results from uncontrolled retrospective and prospective studies suggest that citalopram (42,56,127,128,131), esci-talopram (123), fluoxetine (56,136), fluvoxamine (56), paroxetine (43,129,132,134), and sertraline (56,124,125,133) are effective for the treatment of depression in PD, with the majority of studies investigating citalopram or sertraline. In a prospective, open-label study (n = 62) examining the efficacy of four SSRIs (citalopram, fluoxetine, fluvoxamine, and sertraline) for the treatment of PD depression, all agents were similarly effective (56). Taken together, the data from these uncontrolled studies in depressed PD patients suggest that the efficacy of SSRIs may be a class effect. However, outcomes from controlled studies of SSRIs for depression in PD have been mixed and have also included small numbers of patients (139,140,142-145,147). In one study (n = 32), sertraline and amitriptyline were found to be equally efficacious (139). Fluoxetine has been found to be efficacious (140,142) and, in one study involving 16 patients, efficacy was similar to nefazadone (142). In another study (n = 47), fluvoxamine (mean dose = 78 mg) and amitriptyline (mean dose = 69 mg) were similarly efficacious (147). However, approximately 40% to 45% of patients in each group dropped out due to adverse effects, predominantly confusion and hallucinations. On the other hand, some studies have found no significant difference between sertraline or citalopram and placebo (143,145). In a 10-week controlled study of 12 patients, Leentjens et al. (143) reported a clear treatment effect with sertraline and placebo, but without a significant between-group difference. In a 6-week controlled study (n = 37), Wermuth et al. (145) also reported a significant treatment effect with citalopram and placebo, but a significant between-group difference was not observed. Due to the small sample size, it is possible that these studies were not adequately powered to detect significant differences between study drug and placebo. Thus, based solely on the available scientific evidence, the efficacy of SSRIs for the management of depression in PD appears favorable yet remains unclear. Furthermore, many PD patients remain depressed despite long-term treatment with an SSRI (11). This may be related to use of an inadequate antidepressant dosage, limited efficacy, or poor adherence to medication.

Miscellaneous agents

In addition to SSRIs and TCAs, several other antidepressants are available, including bupropion, duloxetine, milnacipran, mirtazapine, moclobemide, nefazodone, reboxetine, selegiline, trazodone, and venlafaxine. Of these agents, only mirtazap-ine, moclobemide, and nefazodone have been evaluated in a controlled manner for the management of depression in PD (141,142,146). In terms of natural products, high-dose S-adenosyl-methionine was found to be effective for PD depression in a 10-week, open-label, pilot study involving 13 patients (153).

Bupropion, a dopamine reuptake inhibitor, may be effective in PD depression (130). Common side effects include agitation, constipation, dry mouth, excessive sweating, tremor, and weight loss. Uncommon side effects include psychosis and seizures at high dosages.

Mirtazapine is a dual-action antidepressant that augments noradrenergic and serotonergic transmission via antagonism of central a2-autoreceptors. The drug also has antihistaminic properties. In a randomized, double-blind, placebo-controlled study involving 20 depressed PD patients, mirtazapine 30mg/d in combination with brief psychotherapy was superior to placebo in reducing depression (141). Common side effects include constipation, dry mouth, orthostasis, sedation, and weight gain. The incidence of sedation was inversely correlated with dosage. Additionally, uncontrolled data suggest that mirtazapine attenuates parkinsonian tremor and levodopa-induced dyskinesia (154,155). Uncommon side effects include agranulocytosis, hypercholesterolemia, hepatic impairment, hallucinations/psychosis, and rapid eye movement sleep behavior disorder (156,157).

Moclobemide (not available in the United States) is a reversible inhibitor of monoamine oxidase type A (MAO-A), and selegiline is an irreversible, selective inhibitor of monoamine oxidase type B (MAO-B). Inhibition of brain MAO-A activity increases norepinephrine and serotonin concentrations. One small controlled trial (n = 10) compared moclobemide to moclobemide plus selegiline in PD patients with major depression and found a greater benefit with combination of moclobemide-selegiline treatment (146).

In non-PD patients, transdermally administered selegiline is effective and safe for the treatment of major depression (158,159). Through transdermal delivery, selegiline is directly and continuously absorbed into the bloodstream. As a result, initial exposure of the drug to the digestive tract is minimized and lower therapeutic doses allow for levels of selegiline, inhibiting both MAO-A and MAO-B isoforms in the brain to produce an antidepressant effect while sufficiently preserving MAO-A in the digestive tract to break down tyramine. However, at higher therapeutic doses, dietary tyramine modification is required to reduce the risk of hypertensive crisis. To date, no published data are available on the efficacy and safety of transdermal selegiline for the treatment of depression in patients with PD.

Nefazodone and trazodone possess antidepressive and anxiolytic properties. Both agents antagonize 5-HT receptors and modestly inhibit the reuptake of norep-inephrine and 5-HT. In a controlled comparative study (n = 16), nefazodone and fluoxetine were similarly effective at improving depression, with nefazodone also producing a notable improvement in motor symptoms (142). However, the use of nefazodone may be limited by reports of hepatoxicity and significant hepatic CYP450 3A4-mediated drug-drug interactions. Trazodone has not been studied in PD depression; however, low-dose trazodone is commonly used as a sedative/hypnotic. Of note, a metabolite of trazodone, m-chlorophenylpiperazine, is anxiogenic and a subset of patients may experience irritability and enhanced anxiety, especially if trazodone is used in the presence of a potent CYP450 2D6 isoenzyme inhibitor (e.g., fluoxetine and paroxetine) (160). Common side effects of both nefazodone and tra-zodone include dizziness, orthostatic hypotension, and sedation.

Duloxetine, milnacipran, and venlafaxine are dual-action antidepressants that selectively inhibit norepinephrine and 5-HT reuptake, and reboxetine is a selective norepinephrine reuptake inhibitor. To date, there are no published reports on the use of duloxetine for managing depression in PD. Preliminary reports on milnacipran and reboxetine (neither available in the United States) suggest that these antidepressants may be effective in PD patients (121,122,126). With venlafaxine, open-label data (n = 14) suggest that at 75mg/d, it is well tolerated and improves depressive symptoms in patients with PD (125). At low doses, the pharmacologic activity of venlafaxine resembles that of an SSRI and, therefore, an anxiolytic effect can also be expected. At higher doses, norepinephrine reuptake activity becomes more pronounced and an activating effect can be expected. Venlafaxine-induced hypertension has also been observed at higher dosages; therefore, blood pressure should be monitored periodically.

Dopamine agonists

Pramipexole and ropinirole have been reported to have antidepressant properties (161-165). In an 8-month, prospective, randomized study (n=41) comparing the antidepressant effects of pramipexole and pergolide, as an add-on to levodopa in depressed patients with PD, a significant improvement in depressive symptoms was only observed in the pramipexole-treated patients (162). In a prospective, observational study of 657 pramipexole-treated patients with PD, the frequency of anhedo-nia and depression was significantly reduced during treatment with pramipexole (166). In an open-label study with ropinirole and pramipexole, both were shown to improve depression in PD patients (165). In a study enrolling non-PD patients with treatment-resistant depression, ropinirole was added to a TCA or SSRI and demonstrated modest benefit (167). Additional studies on the effect of dopamine agonists on depressive symptoms in PD are warranted.

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