Sertraline 3D chemical structure

Drug of the Month:
Sertraline (Zoloft)

Dopaminergic, safest in heart disease

Biological mechanism

Sertraline is a classic serotonin reuptake inhibitor (SRI), well-known to most clinicians. It’s easy to dose and has a wide range of uses.   

What few know is that it isn’t a pure SRI. It has notable dopamine reuptake inhibition. In some animal studies, its dopamine reuptake blockade is similar to methylphenidate. It’s hard to know whether this mechanism has important clinical effects in humans though.  One would expect weight loss and enhanced sexual function with  such dopaminergic effects, yet these clinical outcomes don't tend to occur in humans. 

Sertraline is the best studied antidepressant in persons with heart disease, and it’s the most proven safest agent in the setting of cardiovascular diseases.  The SADHART study didn’t find that sertraline improved cardiac outcomes, though some analyses suggest some such benefits. But at least it can be stated that it doesn’t worsen cardiac outcomes and has no known cardiac risks.  (The same cannot be said of many other antidepressants, such as bupropion, which has an amphetamine-related structure and can cause worsen hypertension, and possibly increase risk of cardiac arrhythmias; or venlafaxine, which has some association with increased risk of sudden cardiac death, which led to its restriction in the UK so that it is contraindicated in older persons with active heart disease.   

Other features

It is given sublingually.  Despite flavoring attempts, it can be distasteful for some persons. 

Clinical efficacy

It often isn’t appreciated that the randomized trial literature of sertraline in MDD, conducted in the 1990s, was almost entirely outpatient, not conducted in hospitalized patients. Thus, there is no appreciable scientific evidence that sertraline is effective in hospitalized or severe depression. 

It has few drug interactions and can be used without much concern about liver interactions, unlike some other SRIs. 

Fast facts: Sertraline (Zoloft®) 

Typical dose:  50-100 mg/d (range 25-200 mg/d)

Biological mechanism: dopamine and serotonin reuptake inhibition

Typical side effects: sexual dysfunction, diarrhea

Medically important side effects:  none known

Clinically proven efficacy: FDA indications for MDD, OCD, panic disorder, PTSD, social anxiety, premenstrual dysphoric disorder


At low doses (25-50 mg/d) sertraline is more purely serotonergic and has anxiolytic effects.   Its mean effective dose in the MDD studies was about 75 mg/d (with a range of 50-100 mg/d).  Though it can be dosed higher, it hasn’t been proven to be more effective for MDD above 100 mg/d than below that dose. 

The PL Bottom Line

  • Sertraline is a versatile agent, but not proven effective in severe depression  
  • It has dopaminergic mechanisms, but clinical implications are unclear.  
  • It is the most proven safest antidepressant in persons with cardiovascular disease. 

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