Drug consult on “citalopram, methylphenidate, or their combination in geriatric depression” in a “randomized, double-blind, placebo-controlled trial” (Lavrestsky et al. 2015, 561).
Elderly patients with symptoms of depression do not show responses as strong as younger patients to anti-depressants. Lavretsky et al. (2015) note that antidepressant therapies are commonly used to alleviate geriatric depression but many geriatric patients “chronic course or relapse frequently after periods of improvement” (561). The quality of life of elderly patients with depression is often greatly reduced because of cognitive impairment (561). The sufferers may exhibit a low response to treatment, difficulty functioning with essential daily tasks, and their risk of developing dementia becomes higher (561). The reasons for the difficulties are due to age and to dysfunctions of the frontostatial systems in conjunction with the depression (561). The elderly are more likely than younger patients to demonstrate lower response rates to first-line antidepressants as well as approximately 30% emission rates and higher rates of depression recurrence (561). Therefore finding the best anti-depressant treatment is significant in aiding elderly patients to overcome depression.
The purpose of the experiment was to conduct a randomized, double-blind, placebo-controlled trial to identify the efficacy of citalopram, methylphenidate or the combination of the two (561). The independent variables for comparative purposes in the experiment were the mechanisms of action with reference to their dopaminergic functions (561). The dependent variables reported were the clinical and efficacy of the three drug treatments for reduction of depression symptoms in elderly patients (561). (See table 1)
he significance of the research design is that methylphenidate was included for the first time in published research for the random, double-blind, placebo-controlled trial to improve response rates for depression in the elderly (561). The reason for seriously considering methylphenidate in particular was because monotherapy with the anti-depressant has been show to be effective (561). The methylphenidate mechanism for relieving depression is because it is a dopamine reuptake inhibitor (561).
Methylphenidate is sold on the market as Ritalin™ and used to treat children for attention deficit hyperactivity disorder (ADHD) (Volkow et al. RC121, 2001). The mechanisms that produce therapeutic results for ADHD are not well-known (RC121). On the other hand it is known that “methylphenidate blocks the dopamine transporter, (which) is the main mechanism for removal of extracellular dopamine” (RC121). Whether or not therapeutic dosages were appropriate for significantly producing extracellular dopamine in large enough concentrations was not known so Volkow et al. carried out an experiment to find out. The purpose of the experiment was carried out to observe the “increase in extracellular dopamine in the human brain” using “therapeutic doses of oral methylphenidate” (RC121). The experiment was focused to learn efficacy of methylphenidate for ADHD patients, but some symptoms of ADHD and geriatric depression are similar. Higher concentrations of dopamine (DA) were measured and the reason is an interesting mechanism. The researchers reported that “coupled with recent findings of increased dopamine transporters in ADHD patients, which is expected to result in reductions in extracellular DA) provides a mechanistic framework for the therapeutic efficacy of methylphenidate” (RC121). Increases in the DA concentration are caused “by the blockade of dopamine transporters by methylphenidate” was found to be mainly a reflection of an augmentation of the “spontaneously released DA” (RC161). Environmental response occurs following the augmentation of the DA (RC161).
Screening to find the sample was carried out over the telephone. The total number sample was 510 individuals (Lavretsky et al. 562). From the total sample, 203 individuals were asked to take part in diagnostic interview (562). At the diagnostic interview the research was described to the individuals attending with the assumption that they were all potential participants (562).Informed consent forms were signed by the interviewees to guarantee ethical regulations were met (562). The research lasted for 16 weeks (562).
The primary outcome reported the HAM-D scores. The HAM-D scores were continually implemented for the three treatment groups to acquire measurements of residual depressive symptoms improvements (562). Response rates were measured in order to compare the rate of response “by week four” (562). Week four was chosen because the methylphenidate titration ended at the end of week four (562).
The secondary outcome reported the measurements of the comorbid illnesses apathy, anxiety, vascular and medical risk factors were taken. “Health-related quality of life and cognitive performances” were also measured using the HAM-D scale (562). Remission was defined as a secondary outcome when the HAM-D score measured ≤6 (562).
A computer generated schedule based on block randomization algorithms were used to ensure that randomization was embedded into the experiment. Highly careful allocation concealment strategies were undertaken in order to make sure the blind was well-protected. Interior validity for the randomization and the blind for the trial was closely monitored by a researcher created guessing scale.
Methylphenidate titration was carried out during the first four weeks so the participants were seen in –person each week (562). The safety and detection of acceleration was monitored during the first four weekly visits and then every two weeks afterwards for the duration of the experiment (562). The participants were given their medicine each week to last for the whole week from the UCLA Pharmacy (562). The capsules looked the same and the combination dose contained 20 mg/day citalopram and 2.5 mg of methylphenidate or the medication with the placebo two times a day (562). The methylphenidate was applies as a flexible dose, meaning that at concentrations of ranging from 5 mg/day to 40 mg/day. The concentration of the dose was dependent on the “response and tolerability of assessment, which was carried out each week (562). Weekly increases of dosage were dependent upon the Clinical Global Impressions Scale if the improvement score measured ≥3 if no adverse effects had been experienced during the week (562).
Fifty nine participants accounting for 41.3% of the total participants showed treatment resistance (meeting the criteria set by experimental parameters) (563). Mean dosages taken were not significantly different (563). The highest remission rates were measured for citalopram plus placebo when compared to methylphenidate plus placebo. Remission rates reached 69.2% taking a dosage of 60 mg/day citalopram showing a probability of p-=0.02 (564). Remission rates were not significant with methylphenidate with placebo; the highest measured was 58.3% demonstrating a p=0.02 (564).
A post-hoc analysis of the change in HAM-D scores from baseline to clinical trial end showed a higher significance for the citalopram plus methylphenidate group than the other two groups with a p=0.01. In the analysis time was used as the categorical effect, “adjustment for gender” and “baseline medical burden” was made (564).The of methylphenidate plus placebo showed a p=0.02 and with the citalopram and placebo p=0.005.
The rates of change measured with HAM-D were most distinct between the two phases of (a) from baseline to week 4 and (b) from week 4 to week 16 (565). In the second phase from baseline to week 4 the citalopram plus methylphenidate group demonstrated a faster reduction rate for the Mean HAM-D score when compared to the methylphenidate plus placebo compared to methylphenidate plus the placebo group, p=0.04. During the second phase the comparison the citalopram plus methylphenidate group demonstrated no significant change (565). After week 4 the citalopram plus placebo group showed a significantly faster decrease according to the HAM-D scores when compared to the methylphenidate plus placebo (p=0.03).
High participant dropout rates led to non-significant from 12 to 14 weeks (565).
Group differences analyzed by “remission status, partial response status, and non-response status” demonstrated the most favorable combination was the group taking the citalopram plus methylphenidate (p=0.04).
Cognitive Z-score was used for between-treatment comparisons based on composite domain. The Raw Score Change by Neuropsychological Test was used for between-treatment comparison.
The cognitive outcomes with citalopram and methylphenidate combined dose demonstrated “much” improvement and “very high” improvement compared with the groups taking the monotherapy capsules of (with placebos). Outcomes measured by the SF-36 subscale for changes overtime were improved significantly for between-group differences favored the citalopram and methylphenidate group (the combined therapy). The cognitive measurements showed no significant changes when comparing “the baseline neuropsychological performance” (566). But the between-group measurement for the methylphenidate plus placebo, and citalopram and methylphenidate combined therapy showed “significant improvements according to the global performance score. All groups showed improvement in the language sub-category (566). The methylphenidate and placebo demonstrated better executive functioning (566). With-in group measurements for memory and visuospatial functioning demonstrated no changes in any of the group or improvement in cognitive functioning (566).
Citalopram and methylphenidate in combination for treatment of geriatric patients experiencing depression is recommended with some caution. The treatment demonstrated the best outcomes across the range of cognitive tests in general but the probabilities did not fall within the range of 0.02 to 0.05. Therefore although combination treatment also demonstrated improvement in some of the frontostriatal systems dysfunctions associated with late-life depression during the clinical trial more research is necessary.
References
Lavrestsky, H., Reinlieb, M., St. Cyr, N., Siddarth, P., Ercoli, L.M, and Senturk, D. Citalopram, Methylphendidate, or Their Combination in Geriatric Depression: A Randomized, Double-Bind, Placebo-Controlled Trial. American Journal of Psychiatry, 17(6), 561-569. 2015. doi: 10.1176/appi.ajp.2014.14070889
Volkow ND, Wang G, Fowler JS, Logan J, Gerasimov M, Maynard L, Ding Y, Gatley SJ, Gifford A, Franceschi D. Therapeutic doses of oral methylphenidatesignificantly increase extracellular dopamine in the human brain. J Neurosci.2001 Jan 15;21(2):RC121
