This is the largest placebo-controlled medication trial to date in depressed patients with PD, and the first to compare a dual reuptake inhibitor (nortriptyline) and an SSRI (paroxetine CR). It is also the largest controlled trial to show that depression in patients with PD responds to antidepressant treatment. Nonetheless, it is not large by clinical trial standards and must be seen as preliminary.
While preliminary, this trial yielded results that are perhaps surprising and may have significant clinical implications. The treatment effect of nortriptyline was significant for both the overall change in the HAM-D and in the percent responders, while paroxetine CR was not. Furthermore, nortriptyline, when compared directly to paroxetine CR, produced significantly more responders. Nortriptyline was also superior to placebo on many of the secondary outcomes while paroxetine CR was not. The effect size of nortriptyline was large (1.20, based on HAM-D) and the number needed to treat for nortriptyline was 3.5 based on response status. Both active treatments were well tolerated, although paroxetine CR did have significantly more side effects than placebo and nortriptyline did not.
Nortriptyline has been widely used in treatment of depression in the elderly27
and was found in one study to be superior to an SSRI in patients with post-stroke depression.28
The one previous study done with nortriptyline in depressed patients with PD, a small crossover study which used an outcome instrument that is not widely validated, did suggest that the drug is efficacious.29
The etiology of depression in patients with PD is unclear and any explanation of the apparent superiority of nortriptyline would be speculative. While there are significant psychosocial stressors intrinsic to the illness, there are also numerous studies that point to a neurobiological etiology. There is evidence implicating dopaminergic, serotonergic, noradrenergic, and cholinergic dysfunction.30
In addition, changes in trophic and inflammatory factors, such as nerve growth factor and cytokines, which seem to play a role in clinical depression, have also been associated with PD.31
A 2005 PET study30
provided evidence of a loss of noradrenergic neurons in the limbic system in patients with PD and depression, perhaps providing a possible way of understanding these results. Nortriptyline is a dual reuptake inhibitor, that is, it inhibits reuptake of both serotonin and norepinephrine, whereas paroxetine CR, an SSRI, inhibits the reuptake of only serotonin. Thus, it is possible that the mechanism of the apparent superiority of nortriptyline is its effect on norepinephrine.
Another, admittedly speculative, explanation for these results may lie in the role of norepinephrine transporters in the prefrontal cortex. The norepinephrine reuptake transporter is responsible for removing dopamine from the synapse in this area of the brain.32
Blockade of these transporters by agents such nortriptyline can acutely increase dopamine levels in the frontal cortex,33
facilitating dopaminergic function.
At present, it appears that the SSRIs are the first-line choice for depression in PD in clinical practice and that the TCAs are not commonly used.9,10
This study, however, suggests that the SSRI paroxetine CR is not superior to placebo in patients with PD and depression and may be inferior to nortriptyline. The effect size for paroxetine CR on the HAM-D was medium (0.51); a study with a larger sample size or of longer duration might have found a significant effect on this outcome, although paroxetine produced fewer responders than did placebo. These results are consistent with the two previous controlled trials with SSRIs34,35
(sertraline and paroxetine) in PD which, while admittedly methodologically flawed, did not support the efficacy of these compounds. However, there are also numerous open-label studies of paroxetine (non CR)36
and other SSRIs7
in this population that have shown good efficacy and low dropout rates.
While only an 8-week trial, the improvement in the secondary outcomes in this trial is noteworthy. Patients on nortriptyline had significant improvements in physician-rated overall improvement, social functioning, sleep, and anxiety. These improvements are consistent with the descriptive literature in depression that suggests that depression negatively affects these aspects of the patient’s condition. Furthermore, sleep and anxiety are strongly correlated with overall quality of life5
and improvements in these symptoms may be, by themselves, valuable outcomes.
The tolerability and safety assessment included in the trial indicated that both drugs were well tolerated. Both drug treatment arms had similar dropout rates and, although dropout rates of this size are not unusual in psychopharmacologic trials, their size may limit the generalizability of the trial. The side effects were consistent with side effects seen in non-PD populations. Nortriptyline can increase the P–R interval, QRS duration, and Q–Tc
interval and has been associated with cardiac arrhythmias.37
There were, however, no significant effects of nortriptyline on cardiac conduction in this trial. There were also no significant changes in vital signs in any of the groups and neither active drug had negative effects on cognition.
While nortriptyline, given its potential for cardiac conduction delay, needs to be used cautiously, the emerging evidence suggests that its benefits are substantial. The two non-TCA dual reuptake inhibitors that do not have significant cardiac effects, venlafaxine and duloxetine, have not been extensively evaluated in depression in PD. There are ongoing trials evaluating some of these compounds in PD, so we await, with interest, the results of these trials. Further studies, with larger numbers of patients, broader entrance criteria, and antidepressants that effect neurotransmitters other than serotonin, are needed.