Depression is highly prevalent in older adults and those with cardiovascular disease.
Selective serotonin reuptake inhibitors (SSRIs) are generally safe first-line treatments, but many wonder if they’re safe for those with cardiovascular disease.
Key Facts:
- There is insufficient evidence to confirm the safety of most newer antidepressants for older and cardiovascular patients.
- SNRIs like venlafaxine may increase risk of orthostatic hypotension; duloxetine can cause falls.
- Ketamine and esketamine can transiently increase blood pressure to concerning levels.
- With careful administration, second-line agents may still provide alternatives after SSRI failure.
Source: CNS Drugs (2020)
Depression & Cardiovascular Disease Link
Depression goes hand-in-hand with advanced age and chronic health conditions.
Around 20% of cardiovascular patients have major depression, nearly 4 times the rate seen in the general population.
Besides quality of life impacts, depression worsens medical prognosis.
Yet current treatments fall short for many patients.
Selective serotonin reuptake inhibitors (SSRIs) like sertraline and citalopram are well-studied first-line options.
Multiple randomized controlled trials in older and heart disease patients support their safety and provide modest evidence of benefit.
However, efficacy is far from complete. Up to two-thirds fail to achieve remission on the first SSRI tried. Side effects also frequently limit use.
Clearly there is need to look beyond SSRIs for those not responding.
But newer agents generally lack evidence in these vulnerable groups.
Researchers reviewed cardiovascular safety data for 12 prominent non-SSRI medications, noting any red flags that require caution.
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) & Cardiovascular Disease
Of the 12 agents evaluated, 5 fall under the SNRI class: venlafaxine, desvenlafaxine, duloxetine, milnacipran and levomilnacipran.
SNRIs dually boost serotonin and norepinephrine signaling.
Compared to SSRIs, some offer advantages like reduced sexual side effects or dual benefits for pain.
However, norepinephrine-mediated changes in blood pressure and heart rate may raise cardiovascular concerns.
Venlafaxine: Reasonably Safe Aside From Orthostatic Hypotension Risk.
Marketed under brand names Effexor/Effexor XR, venlafaxine only acts on norepinephrine at higher doses above 150mg.
Thus, low-dose regimens may avoid such cardiovascular liabilities seen with duloxetine and other balanced SNRIs.
Small trials show minimal effects on blood pressure or electrocardiogram (ECG) parameters during short-term use.
However, up to 50% of elderly subjects exhibited orthostatic hypotension, defined as an excessive drop in blood pressure on standing.
The potential fall risk warrants caution with this particular side effect.
But otherwise, venlafaxine appears no less safe than SSRI options like citalopram for seniors based on head-to-head data.
Desvenlafaxine/Pristiq: Insufficient Evidence in At-Risk Patients.
Desvenlafaxine is a metabolite of venlafaxine.
It may have similar properties, but evidence confirming this is severely limited in older and heart disease groups.
One short trial in older patients hinted at minor blood pressure elevations in a minority.
But uncontrolled study design prevents drawing safety conclusions. Further data is critically needed.
Duloxetine/Cymbalta: Risk of Falls Despite Minimal Vital Sign Effects.
Duloxetine is considered the most balanced SNRI in terms of serotonin/norepinephrine action.
But unexpectedly, clinical trials display only small effects on blood pressure or heart rate among seniors.
No clinically concerning ECG changes emerged either.
However, one meta-analysis associated duloxetine with significantly increased fall rates in the elderly.
The mechanism is uncertain but may involve medication-induced dizziness or orthostatic hypotension in subset of vulnerable individuals.
Careful supervision is advised to minimize harm, especially early after duloxetine initiation or dosage escalations.
Milnacipran/Savella & Levomilnacipran/Fetzima: Critical Knowledge Gaps.
Milnacipran and levomilnacipran likewise show balanced SNRI properties.
But almost nothing has been published examining their safety in older patients or those with heart issues.
Without further RCT evidence, their use cannot be recommended in these groups at this time.
Atypical Antidepressants & Cardiovascular Disease Risk
Beyond SSRIs and SNRIs, some agents have less easily categorized mechanisms of action.
Three such examples are mirtazapine, bupropion and vortioxetine.
Each modulates signaling of serotonin and sometimes other monoamines through unconventional pathways compared to standard choices.
Mirtazapine/Remeron: Reasonably Safe But Weight Gain Concerning
Adding mirtazapine or the SSRI paroxetine showed no differential impact on vital signs or ECGs in one 16-week senior trial.
Together with low risk for cardiac events in post-heart attack patients, these findings offer some degree of reassurance.
However, in contrast to SSRIs, mirtazapine often substantially increases appetite and weight.
The resulting metabolic changes may indirectly heighten cardiovascular risk over the long-term.
Whether this possibility translates into clinical events like myocardial infarctions or strokes remains speculative based on available data.
But the obesity-related concerns should limit mirtazapine use to clear-cut depression refractory to other safer options.
Bupropion/Wellbutrin: Studies Too Short for Confidence in High-Risk Groups
Marketed under the brand name Wellbutrin, bupropion represents an unusual, non-monoamine antidepressant.
Through poorly understood mechanisms, the drug enhances both dopamine and norepinephrine neurotransmission.
As might be expected, short-term trials note small increases in blood pressure among heart patients on high-dose (600mg) regimens.
However, studies longer than 3 months are conspicuously absent in the literature.
With no assurance that cardiovascular liabilities might emerge later, prolonged use cannot be endorsed in seniors or other vulnerable groups until more data accrues.
Vortioxetine/Trintellix: Initial Evidence Supportive But Confirmation Needed
Vortioxetine has complex serotonin-modulating properties.
Though prescribed for depression, how it exerts antidepressant efficacy remains uncertain.
Initial 8-week data showed excellent tolerability among seniors in terms of blood pressure, heart rate and ECGs during treatment with low 5mg daily doses.
Still, confirmatory evidence with longer follow up and higher dosing is essential to support use in at-risk cardiology patients.
Other Novel Antidepressants & Cardiovascular Effects
Lastly, the review examined miscellaneous agents like the sleep-regulating drug agomelatine and rapid-acting intravenous ketamine.
As rising choices for tough-to-treat depression, their place in management deserves consideration.
Agomelatine/Valdoxan: Thus Far Safe But Study Populations Too Limited
Agomelatine targets melatonin pathways.
Available in Europe, Australia and elsewhere (though not the US), the drug showed no concerning impact on cardiovascular parameters over 8-12 week trials in older patients and younger heart disease sufferers.
However, only the brief geriatric study employed a randomized, placebo-controlled design to account for underlying cardiac changes unrelated to the drug.
More rigorous testing is still needed before clinicians can feel comfortable prescribing agomelatine alongside other risk-raising medications in vulnerable patients.
Ketamine/Esketamine: Caution Warranted Due To Transient Blood Pressure Elevations
Unlike other covered drugs, ketamine provides near-instant relief from severe or suicidal depression.
However, anesthetic doses raise blood pressure considerably as part of their neuronal effects.
Studies using low-dose intravenous regimens for depression likewise indicate routine though transient systolic elevations averaging only around +3mmHg among largely middle-aged, healthy subjects.
Elderly patients and those with baseline hypertension saw somewhat exaggerated peaks.
Nonetheless, such minor, self-limited spikes rarely required intervention.
Recently approved as an intranasal spray for treatment-resistant depression, esketamine likewise causes dose-related blood pressure rises, usually peaking around 40 minutes post-administration.
Similar to ketamine, the acute effects dissipate within 1-2 hours without incident.
Although statistically increased compared to placebo, the transient magnitude of change falls below thresholds typically felt to endanger cardiovascular stability acutely.
However, the long-term consequences of repeatedly evoking such episodes remain completely unknown.
Since ketamine and esketamine fill an important niche for patients failed by other therapies, further studies should urgently evaluate whether periodic exposure leads to higher risk over months or years.
Takeaways: Balancing Depression Treatment with Cardiovascular Uncertainty
Currently available research leaves much unknown regarding cardiovascular safety and efficacy of second-line antidepressant medications in high-risk groups.
For most agents discussed, elderly and heart disease populations have simply never been evaluated in controlled trials spanning longer than a few months.
Nevertheless, depression severely impacts quality of life while also worsening medical prognosis.
With suicidality especially heightened in patients who cannot access relief through standard SSRI therapies, the harm versus benefit calculation warrants thoughtful appraisal.
In combination with vital sign monitoring and dose adjustments as needed, judicious use of secondary agents like venlafaxine, duloxetine or mirtazapine may still allow individualized treatment plans able to successfully walk the line between efficacy and safety.
Moving forward, however, sponsors and drug developers shoulder the responsibility to specifically demonstrate that novel depression therapies meet the needs of maximum-risk cardiology patients through dedicated clinical trials.
References
- Study: The cardiovascular effects of newer antidepressants in older adults and those with or at high risk for cardiovascular disease
- Authors: Behlke et al. (2020)
