Escitalopram for Major Depression in Parkinson’s Disease: An Open-Label, Flexible-Dosage Study

Subjects were patients with Parkinson’s disease who were being seen for routine psychiatric care or were screened for depression as part of an ongoing research study at the Parkinson’s Disease Centers at the Philadelphia Veterans Affairs Medical Center (PVAMC) or the University of Pennsylvania. Patients with a diagnosis of possible or probable idiopathic Parkinson’s disease, 19 confirmed by a movement disorders specialist (M.B.S. or J.D.), a Mini-Mental State Examination (MMSE) 20 score of >24, a DSM-IV diagnosis of a major depressive episode when interviewed with the Structured Clinical Interview for DSM-IV (SCID), 21 and a 24-item Hamilton Depression Rating Scale (HAM-D) 22 score of ≥16 met primary study inclusion criteria. Exclusion criteria included a recent history of substance abuse or any other DSM-IV Axis I diagnosis besides major depression. Patients taking stable doses of benzodiazepines were allowed to participate. For patients taking an antidepressant at screening, a 2-week washout period was necessary before baseline (4 weeks for fluoxetine). An inclusive scoring method was used for all diagnostic and rating instruments. The study was approved by the PVAMC and the University of Pennsylvania Institutional Review Boards, and all subjects gave written informed consent.

The study was a 12-week open-label trial of escitalopram. Subjects started a regimen of escitalopram at 10 mg/day, and the dosage was increased to 20 mg/day after 4 weeks if treatment was well-tolerated and the subject had not been rated as “very much improved” or “much improved” on the Clinical Global Impression-Improvement (CGI-I). 23 The dosage could be decreased to 5 mg/day at any point, if clinically indicated. Study visits were at end of Weeks 2, 4, 6, 8, and 12.

At baseline and all study visits, a trained research assistant administered the Hamilton Depression Rating Scale (HAM-D), Inventory of Depressive Symptomatology (IDS), 24 and Hamilton Anxiety Rating Scale (HAM-A). 25 The Apathy Scale 16 and the Center for Neurologic Study–Lability Scale (Lability Scale) 26 were administered at baseline and at study completion. The principal investigator (Dr. Weintraub) administered the Unified Parkinson’s Disease Rating Scale (UPDRS), 27 including the Hoehn and Yahr stage, 28 four times during the course of the study and the CGI-I at all post-baseline visits without knowledge of any other study ratings.

We also assessed patients with a series of neuropsychological instruments at baseline and study completion, including the MMSE, Hopkins Verbal Learning Test–Revised (HVLT-R), 29 Tower of London-Drexel (TOL ^DX ), 30 and Trail Making Test A and B (TMT-A and TMT-B). 31 The HVLT-R assesses verbal learning and memory; TOL ^DX assesses planning, problem-solving and working memory; TMT-A assesses psychomotor speed; and TMT-B assesses mental tracking and cognitive flexibility.

A priori, the primary outcome measures were designated as the change in the IDS score and the final CGI-I score, and the change in HAM-D score was a secondary outcome measure for depression. The IDS is a 30-item instrument (scores ranged from 0 to 84, higher scores indicating greater severity of depression) that covers a broader range of depressive symptoms than the HAM-D 32 and therefore may possibly be a more sensitive instrument for measuring depression severity.

Intent-to-treat analyses with last observation carried forward were performed, and all subjects who took at least one dose of study medication were included (N=14). Response for the primary outcome measures was set as a ≥50% decrease in IDS score or a score of 1 or 2 on the CGI-I, while remission was set as an IDS score <14, as recommended. 24 For the HAM-D, response was set as a ≥50% decrease in score, and remission was set as a score ≤8. For the IDS, HAM-D, and HAM-A, repeated measures of analysis of variance (rANOVA) were performed and 95% confidence intervals (CIs) were calculated for the change in score; for all other measures, we performed the Wilcoxon signed-ranks test. For correlations, we used Spearman’s rank correlation (r _s ). As this was a pilot study to probe for moderators of treatment response, we did not make a correction for multiple comparisons; a p value of <0.05 was considered significant.

Fourteen subjects (13 men, one woman) entered the clinical trial, and 12 completed it. Mean values included: age =72.1 (SD=8.0) years, duration of Parkinson’s disease=5.4 (SD=4.3) years, Hoehn and Yahr stage =2.8 (SD=0.5), and years of education =14.0 (SD=2.6).

Based on baseline IDS and HAM-D values, subjects on average had major depression of moderate severity ( Table 1 ). They also experienced elevated levels of anxiety, apathy, and affective lability. Cognitively, subjects scored in the average range on the MMSE and the HVLT-R (z=–0.53 and −0.80 on the HVLT-R immediate and delayed free recall tests, respectively), but had low average or impaired scores on tests of executive function (z=–1.33 on TMT-B; z=1.69 on TOL ^DX -TMS; z=2.14 on TOL ^DX -EXTS).

There were significant decreases in both IDS (F=4.29 _5,9, p=0.03) and HAM-D (F=7.77 _5,9, p<0.01) scores over the course of the study ( Table 1 and Figure 1 ). The mean decrease in IDS score was 7.8 units (95% CI=3.0, 12.6), equivalent to a 25.9% decrease. Similarly for the HAM-D score, the mean decrease was 7.5 units (95% CI=3.1, 11.9), equivalent to a 37.7% decrease over the course of the study.

Examining rates of response and remission, 21.4% of subjects met criteria for response and 14.2% for remission using the IDS, and 35.7% met criteria for both response and remission using the HAM-D (i.e., all HAM-D responders were also remitters). On the CGI-I, 50.0% of subjects met criteria for response, with no subjects reporting worsening in their condition.

All significant improvement in depression occurred by either Week 4 (using the HAM-D) or Week 6 (using the IDS) ( Figure 1 ). All but one of the seven subjects who were rated as responders on the CGI-I had achieved this score by Week 6.

There was a suggestion of a decrease in HAM-A score with treatment (F=3.4 _5,9, p=0.05), with a mean decrease in score of 2.7 units (95% CI=0.7, 6.1), equivalent to a 22.2% decrease, but there were no changes in the Apathy Scale or Lability Scale with treatment ( Table 1 ). Regarding cognition, there were no changes in global cognition (i.e., MMSE score), memory, or executive function over the course of the study.

There were no significant changes in motor symptoms or psychomotor speed with escitalopram treatment, though there was nearly a five-point drop in the total UPDRS motor score and a suggestion of improvement on the tremor and rigidity subscales ( Table 1 ). In addition, the mean daily L -dopa dosage remained the same (459 versus 512 mg/day, z=–1.1, p=0.27). Regarding adverse events, two subjects terminated within several days of starting antidepressant treatment due to worsening of baseline nausea and confusion, respectively. All subjects who completed the study were able to tolerate either 10 or 20 mg of escitalopram daily.

We examined the association between baseline clinical characteristics and improvement in depression for 12 variables (Apathy Scale, 1 Lability Scale, 1 HAM-A, 1 HVLT-R scores, 3 TOL ^DX scores, 2 and UPDRS subscores 4 ). Higher Apathy Scale (r _s =–0.66, p=0.01) and lower HVLT-R delayed free recall (r _s =0.68, p<0.01) scores at baseline were associated with less improvement on the IDS. Regarding motor symptoms, greater baseline postural instability was associated with less improvement in HAM-D (r _s =–0.56, p=0.04) and IDS (r _s =–0.58, p=0.03) scores.