Major Depressive Disorder
Lackluster Response to SSRIs: What to Make of Patient Age?
Age-related differences in response to antidepressant therapies may be significant and clinically meaningful. Current treatments for major depressive disorder (MDD) yield remission rates around 30% to 40%, and even in patients with remitted depression, residual cognitive dysfunction can lead to impairment in psychosocial functioning. The cognitive tolerability profile of selective serotonin reuptake inhibitors (SSRIs) in the long term is still an open question for researchers. And, since functional recovery ‒ in addition to symptomatic recovery ‒ is a main target in MDD treatment, there is now growing interest in therapies that may be efficacious for cognitive dysfunction in patients with MDD, young and old.
Q: An older patient with MDD and cognitive dysfunction (but no evidence of dementing illness) responds partially to an adequate trial of SSRI therapy, but the cognitive dysfunction persists. What are your thoughts?
Professor of Psychiatry and Pharmacology
When people hear “cognitive dysfunction in depression” there is sometimes still this association, and they often jump to thinking about dementing conditions. Now, there is no question that people with MDD, especially if it is recurrent, are more susceptible to dementing disorders. We are talking about a phenotype that clearly overlaps, but is very, very different.
Professor of Psychiatry
Yes, and obviously, in the elderly, the possibility of concomitant cognitive impairments associated with vascular events and with dementias is real, and that is something that should be pursued in the differential diagnosis. But that doesn’t mean that elderly patients with depression would require different assessments for cognition in depression. There, I think it is the same: working memory, reaction time, etc, and these deficits need to be measured if we are going to make an impact.
Now, in regard to SSRIs, I think it is becoming clear that the serotonin reuptake blockers do not seem to be as significant in their impact directly on cognitive performance and cognitive function. There are short-term and long-term studies that may begin to give us some explanation, some based on the fact that the cognitive performance and cognitive function effects relate to the efficacy of SSRIs. The other piece is that there is a proportion of patients – probably small, but significant – for whom continued serotonin reuptake blockade may actually lead to some associated apathy and cognitive performance issues. That phenomenon, I think, is something that we’ve known about for some time, and I think it plays out in terms of long-term studies with SSRIs.
I’d have to agree with that, Dr Trivedi, while the evidence is insufficient to allow one to say, with the utmost of certainty, that SSRIs don’t improve cognition. SSRIs, as a broad class, are unequivocally capable of reducing anxiety and dysphoria, and perhaps one could extend that into a sort of affective reactivity, or maybe even an affective impulsivity, in some people. And that overlaps with – but is different from – general, cold, cognitive processes. I think SSRIs have not been subjected to the appropriate level of scrutiny, with the appropriate study design, etc. There is reason to believe there may be some improvement in cold cognitive processes with SSRIs, with the caveat that the study designs are very much limited, in terms of interpretability, vis-à-vis direct effects and pseudospecificity and that kind of thing.
When I approach someone who is elderly, the guiding principles would not be different, fundamentally, from those in the approach to someone who is 25 or 35 years old. There is obviously a differential diagnosis process that needs to take place, and then there are those factors that are modifiable and those that are not.
Distinguished Professor of Psychiatry Emeritus
I’d echo your introductory remarks, Dr McIntyre, and yours as well, Dr Trivedi. I also think it’s an interesting conversation, ie, the extent to which depression may represent a true risk factor for the subsequent onset of one or another form of dementia, and/or be a warning sign, or a kind of prodromal expression of dementia. We certainly have seen both.
My sense from the literature is that patients with longstanding depression, particularly recurrent episodes of clinical severity, are at risk for developing cognitive impairment and frank dementia – whether Alzheimer’s dementia or vascular dementia. Going back to the question in this scenario, however, we are fairly certain that these are the cognitive symptoms of MDD, and not deficits that are primarily due to iatrogenic causes or a different chronic illness – it should be noted, however, that these other causes may be especially significant in older adults. For instance, I believe my colleagues who are geriatric medicine internists pay a lot of attention to de-prescribing, particularly of anticholinergic medications, and other drugs on the American Geriatrics Society (AGS) Beers Criteria list.
Chief, Division of Geriatric Psychiatry
Agreed. I also differentiate between 2 different groups of patients with MDD: 1) those who developed depression when they were in their 20s and 30s and now have aged into their 60s, 70s and now have a recurrent episode and are experiencing cognitive symptoms; and 2) those who are developing depression for the first time later in life, and in association with the depression, they are now having symptoms of cognitive impairment – whether it’s attentional disturbances, or executive dysfunction.
SSRIs like sertraline and fluoxetine have been around since the late 80s and early 90s, then came the SNRIs like venlafaxine and duloxetine. These are all monotherapy drugs, they all work well – perhaps equally well for depressive symptoms – in any age range.
If you go beyond the SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRIs), mirtazapine is a noradrenergic-specific serotonergic antidepressant, or NaSSA. That’s a drug within its own class that is particularly effective for older adults with depression who experience prominent anxiety, poor appetite, and sleep disturbance. Bupropion impacts norepinephrine and dopamine neurotransmission and improves energy and motivation for patients with depression. But it may exacerbate the anxiety that is often co-morbid with depression. There are some medications that work on dopamine, predominantly psychostimulants such as methylphenidate.
Often cognitive deficits are occurring in the context of the depression episode, but once the depression is treated effectively, those deficits improve but may not completely normalize.
Vortioxetine, a serotonin receptor modulator and stimulator, may improve attention and processing speed in older patients with depression. There is one study of vortioxetine at a dose of 5 mg a day that demonstrated this improvement in attention and processing speed in older patients with depression, although clinically a higher dose range may be required for therapeutic efficacy.
Q: What, then, would you describe as an adequate trial of SSRI therapy for the patient in this scenario?
If you have treated a patient with an SSRI for 4-6 weeks at maximum dosage without adverse effects or significant improvement in depression symptoms, then it is probably time to switch to another antidepressant medication. Some of my colleagues argue that, in late-life depression, waiting a total of 12 weeks before switching or augmenting would be preferable, since a longer time to treatment effect is observed with advancing age. Some people would say that we should switch before we augment, in almost every case, because the goal – at least in late-life therapy – is monotherapy treatment to remission, before we start combining therapies. As clinicians, especially if an individual’s residual symptoms are severe, we may not be as patient as we may need to be. In an older adult, we may wait 8-12 weeks instead of 4-6 weeks before switching or adding-on (as we may in a younger adult).
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