Question explored with the scientific record
Tricyclic anti depressants
The short version: tricyclic antidepressants work for severe depression but carry a real cardiac risk that the newer drugs partly avoid.
The evidence here is a mixed sample. The 2013 meta-analysis pooled data from 20 trials comparing TCAs, SSRIs, and placebo for chronic depression and dysthymia [1]. It found no clear difference in efficacy between TCAs and SSRIs -- both drug classes beat placebo roughly equally. What the meta-analysis did show clearly: SSRIs were better tolerated [1]. That is not a trivial result. When two drugs work about the same, the one with fewer side effects wins for most people.
The cardiac risk is the real concern. Multiple records show TCAs block the HERG potassium channel, which is the heart's electrical safety gate [4, 5]. The IC50 values in the evidence -- about 3 to 6 micromolar for imipramine, doxepin, and clomipramine -- means these drugs hit that channel at concentrations that overlap with therapeutic blood levels [4, 5, 9]. The result is QT interval prolongation, which can trigger a dangerous heart rhythm called torsades de pointes. A 2022 review names TCAs alongside a few other drugs as needing special caution for this reason [8]. A 2012 longitudinal study of 2838 people found TCAs increased cardiac sympathetic activity (a sign of stress on the heart) while SSRIs decreased it [6]. The same study found TCAs shortened the pre-ejection period by 11 milliseconds, which is a direct measure of how much the sympathetic nervous system is driving the heart [7].
The suicide risk evidence is worth noting. A 2005 meta-analysis of over 87,000 patients found SSRIs increased suicide attempt risk compared to placebo(odds ratio 2.28), but when compared directly to TCAs, the risk was not statistically different [2, 3]. The number needed to treat to harm for SSRIs was about 1 in 684 patients [3]. This means TCAs carry at least as high a risk of suicide attempts as SSRIs, and possibly higher given the published numbers from the trials.
My call: TCAs work for severe depression -- the 2013 meta-analysis confirms they beat placebo clearly [1] -- but the cardiac risks are real and documented in a human study with over 2800 participants [7]. The side effect burden is worse than the alternatives. For a first-line patient with no cardiovascular risk, SSRIs are the safer choice based on this evidence. Confidence: moderate. The evidence is strong on the mechanism of cardiotoxicity but thin on long-term head-to-head safety studies between classes.
Sources used 9
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Selective serotonin reuptake inhibitors and tricyclic antidepressants in the acute treatment of chronic depression and dysthymia: A systematic review and meta-analysis
This 2012 systematic review and meta-analysis evaluates the efficacy and acceptability of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) in acute treatment of chronic depression and dysthymia, finding that both drug classes are effective ver…
DOI: 10.1016/j.jad.2012.06.007 -
Association Between Suicide Attempts and Selective Serotonin Reuptake Inhibitors: Systematic Review of Randomised Controlled Trials
A systematic review of randomized controlled trials assessing whether selective serotonin reuptake inhibitors (SSRIs) are associated with an increased risk of suicide attempts, finding higher odds with SSRIs versus placebo or non-SSRI comparators but no clear excess when compare…
DOI: 10.1016/s0022-5347(05)00885-2 -
Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials
This systematic review of randomized controlled trials found a significant association between the use of selective serotonin reuptake inhibitors (SSRIs) and an increased risk of suicide attempts, highlighting the need for careful monitoring of patients on these medications.
DOI: 10.1136/bmj.330.7488.396 -
Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitriptyline
This study investigates the reversible inhibition of HERG potassium channels by the tricyclic antidepressants imipramine and amitriptyline, revealing their potential role in prolonging the QT interval and increasing the risk of cardiac arrhythmias.
DOI: 10.1038/sj.bjp.0702800 -
Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin
This study investigates the inhibitory effects of the tricyclic antidepressant doxepin on the HERG potassium channel, revealing significant blockade with implications for QT interval prolongation and cardiac arrhythmia.
DOI: 10.1016/j.bcp.2007.04.024 -
Effects of Antidepressants, but not Psychopathology, on Cardiac Sympathetic Control: A Longitudinal Study
This longitudinal study investigates the effects of antidepressant use on cardiac sympathetic control, revealing that while antidepressant-naïve individuals with depression or anxiety do not exhibit increased sympathetic control, those using tricyclic or serotonergic/noradrenerg…
DOI: 10.1038/npp.2012.107 -
Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in humans
Systemic desipramine acutely lowers whole-body norepinephrine spillover and skeletal muscle sympathetic nerve firing, but increases cardiac norepinephrine spillover, indicating central inhibition of sympathetic outflow combined with organ-specific uptake blockade.
DOI: meta/10.1152/ajpregu.1991.260.4.r817 -
QT interval prolongation, torsades de pointes and psychotropic medication
A descriptive review of QT interval prolongation and torsades de pointes associated with psychotropic drugs concludes that QT prolongation is a useful but imperfect risk marker and that special caution is needed with older antipsychotics, tricyclic antidepressants, citalopram/es…
DOI: 10.24283/hjns.202215 -
Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Various Antidepressant Drugs
This study investigates the inhibitory effects of various antidepressants on G protein-activated inwardly rectifying K+ channels (GIRK) using Xenopus oocyte expression assays, revealing that tricyclic antidepressants significantly reduce GIRK channel activity, which may contribu…
DOI: 10.1038/sj.npp.1300484