Depression is very common in the elderly population and is often under-treated. Symptoms of depression include low mood, loss of interest, energy and concentration, poor sleep and appetite as well as any preoccupation with health problems. When depression interferes with activities of daily function or is associated with safety concerns (e.g. suicidal risk or self harm), treatment is strongly indicated. However conventional treatment options are sometimes ineffective or inadequate, given the clinical manifestation can be different or atypical. Depression may be part of a disease progression related to cognitive impairment or Parkinson’s disease, or it could be a complication from other co-morbidities (e.g. post stroke depression).

While the first line of treatment option is the usual SSRI (selective serotonin re-uptake inhibitor) such as citalopram, escitalopram, sertraline, treatment response may be sub-optimal with monotherapy. Further, dose titration is usually limited in the elderly population due to concerns with risk of falls or adverse effects (e.g. QT prolongation). In these cases, it may be reasonable to add a second agent.

One novel approach is to add a stimulant (methylphenidate). Here’s a one clinical trial that supports its use:

combo-of-citalopram-with-methylphenidate

This is a double blind placebo controlled trial evaluating the potential of adding methylphenidate to improve antidepressant response to citalopram in the elderly population:

study-design

Here are some highlights of the study:

  • Inclusion criteria:
    • a current episode of unipolar major depressive disorder according DSM-IV-TR criteria
    • a score ≥ 16 on the 24-item Hamilton Depression Rating Scale (HAM-D)
    • a score ≥ 26 on the Mini-Mental State Examination (MMSE)
  • Exclusion criteria:
    • history of any psychiatric disorder other than unipolar major depressive disorder with or without comorbid anxiety symptoms,
    • severe or acute unstable medical illness including presence of atrial or ventricular arrhythmia,
    • acute ischemic features on baseline ECG,
    • acute suicidal or violent behaviour or history of suicide attempt within the past year
    • any other CNS diseases
  • Primary outcome measures:
    • Improvement in residual depressive symptoms using continuous HAM-D scores
    • Rate of response by week 4: this corresponded to methylphenidate titrate schedule that ended at week 4
  • Secondary outcome measures:
    • Comorbid symptoms of anxiety, apathy, medical and vascular risk factors, health-related quality of life, and cognitive performance.
    • Remission was analyzed and was defined as a score ≤ 6 on the HAM-D

Results

The primary outcome results are summarized in the graph below. As illustrated, one can see the greatest  reduction of the HAM-D score was with the combination treatment group with citalopram plus methylphenidate (depicted in green).  The rate of response by week 4 can also be seen in the graph. result-graph

Percentage with Remission by end of study:

  • Citalopram + Placebo 20/48; 41.7%
  • Methylphenidate + Placebo 14/48; 29.2%
  • Citalopram + Methylphenidate 29/47; 61.7%

*Results are statistically significant (X² =9.2; df; 2, p=0.01)

In terms of the results for the secondary outcomes, the citalopram plus methylphenidate group achieved the highest percentage of remission.In all treatment groups, there were no significant differences observed in anxiety, apathy and psychological resilience. However, study groups treated with methylphenidate have seen some improvement in cognition, language and executive function.

Here are my thoughts:

  • This study enrolled elderly patients who were depressed but relatively intact in terms of their cognition (MMSE > 26) so I highly question if these results can be applied in the dementia population.
  • Interestingly, the results suggest methylphenidate may improve cognition, language and executive function despite having a population with relative intact cognition. I wonder if it may have a role in dementia prevention that is worth exploring.
  • The results do suggest that treating patients with citalopram plus methylphenidate may offer quicker remission than with citalopram plus placebo or with methylphenidate plus placebo  but there are limitations to keep in mind.
  • The average study dose of citalopram was 30mg/day. This dose is much higher than what is now recommended by Health Canada (20mg/day) so we may not be able to observe the same extent of clinical improvement in our real world setting.
  • It is also unclear how methylphenidate may expedite remission in this study. It is thought to be acting as a dopaminergic agent. If this is the proposed mechanism of action, I wonder if another dopaminergic agent such as premipexole or levodopa-carbidopa would be helpful, or reducing any existing anti-psychotic may offer equally effective response. This is only my speculation and would be difficult to understand at this point.
  • I find it interesting that none of these agents appeared to be helpful in anxiety and apathy, both of which are symptoms that are common and often the reason to start pharmacological therapy.
  • I have seen methylphenidate used in my practice with mixed results.  If the first line agent with selective serotonine reuptake inhibitor (e.g. citalopram) does not provide an adequate response, we do have other agents such as buproprion, mirtazapine, duloxetine, venlafaxine that offer to target different receptors for boosting other neurotransmitters such as norepinephrine and dopamine.
  • The results of this study basically offer another option to consider as an add on therapy in depression for the elderly.  The study provides some clinical experience with its use in the elderly population. However, it should not be interpreted as evidence of efficacy which will require additional studies to establish.

 

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