In most cases, Zoloft (sertraline) is considered the go-to SSRI for adult patients. The medication is well tolerated, has a good safety profile, and robust efficacy data that supports its FDA approvals for major depressive disorder (MDD), obsessive-compulsive disorder (OCD), panic disorder (PD), post-traumatic stress disorder (PTSD), social anxiety disorder (SAD), and premenstrual dysphoric disorder (PMDD). It is FDA-approved for pediatric patients ages 6 to 12 at doses of 25 mg daily and 50 mg daily for children ages 13 and older. It is common practice to use it off-label for generalized anxiety disorder, but does not carry an FDA-approval for this condition and is not my first choice for treating anxiety.
The dosage range of Zoloft for adult patients is 25 to 200 mg daily. Its half life is 24 to 36 hours. The medication is metabolized through phase I metabolism through the cytochrome P450 metabolic pathway via CYP2C19, with small amounts through 2D6 and 3A4. At doses 150 mg daily and higher, it becomes a moderate inhibitor of CYP2D6.
Zoloft’s primary mechanism of action is its strong affinity for inhibiting serotonin transporter (SERT), increasing serotonin availability in the synaptic cleft. As I explain to patients, we are changing the way the brain manages serotonin to leave more available to improve mood and relieve depressive symptoms. This action is what gives Zoloft the FDA approvals mentioned above.
With regard to downstream effects, Zoloft has mild-to-moderate inhibitory activity at the dopamine transporter (DAT) and, to a lesser extent, the norepinephrine transporter (NET)—particularly in the prefrontal cortex, where dopamine reuptake occurs largely via NET and DAT. The downstream action is what contributes to its improvement in symptoms such as low energy, decreased motivation, and problems with concentration and focus.
Like most SSRIs, Zoloft is typically dosed in the mornings because it can be activating in nature. Patients are always concerned about when to take it and while I explain it is best to take it in the morning, it is patient specific. If the patient reports they prefer to take it at lunch or the medication causes some sedation, I instruct it will not hurt to take before bed. More important than timing is consistency and that best practice is to take it at the same time everyday to maintain constant serum levels, so the therapeutic effect is optimized.
I recommend taking Zoloft with food. Most medications, especially serotonergic medications, have the propensity to cause gastrointestinal upset effects such as nausea. While this is worse in the induction and initial titration phase, it is significantly reduced by taking with food. I point out this does not mean a patient has to eat Thanksgiving dinner, just something on the stomach to limit annoying side effects.
I start at 25-50 mg daily and increase by 25-50 mg per day increments weekly. My start low and go slow approach is to start a daily dose and give it four weeks to gauge tolerability before increasing. However, with patients with more severe illness, it is not uncommon for me to start at a dose for a week or two and increase it for more rapid action. Lower doses, such as 25-50 mg daily, are more common when used for anxiety or in geriatric patients. I typically shoot for a dosage range in an adult patient between 50 and 100 mg daily.
I have found moderate to high doses, 100 to 200 mg daily, are more effective for complete antidepressant effect and as is the case with all SSRIs when treating OCD, the dose lands in the higher range. As noted, my toxicology senses activate when dosing 150 mg daily or higher due to CYP2D6 inhibition. The activation of Zoloft tends to be more dose-dependent, which is something to consider with an anxious patient or if there are concerns for hypomania or mania.
Zoloft is remarkably well-tolerated but it is not immune from gastrointestinal upset effects, as mentioned. I tend to see more diarrhea than nausea upon therapy initiation. This and activation are among the most common complaints, which are often dose-dependent. The sexual side effects (also dose-dependent) of erectile dysfunction, decreased libido, and delayed orgasm or anorgasmia are the typical reason patients will discontinue the medication. The unfortunate thing about sexual side effects, is they can persist, while many other side effects will abate as the patient’s body adapts. As is the case with sexual side effects, I explain to patients they can happen and every patient is different. If they do occur, it does not mean the only solution is to stop the medication, especially if it helping. Sometimes dose reduction will clear the side effects and in the case of erectile dysfunction, prescribing a phosphodiesterase 5 (PDE5) inhibitor like Viagra (sildenafil) is all it takes to remedy the side effect (careful with any patient taking nitrates, especially geriatric patients).
In terms of how Zoloft compares to other SSRIs with regard to sexual side effects, I see it much less than I do with Paxil and consider it less likely to cause sexual side effects than Celexa or Luvox. Sexual side effects with Zoloft can be more common than with medications such as Prozac or Lexapro.
Like all SSRIs, the therapeutic effect with Zoloft is not immediate. While the inhibition of SERT and increased serotonin levels starts with the first dose, it still takes 4-8 weeks before the therapeutic effect is seen. I tell patients they may start to notice a difference within 2 weeks but treatment is a marathon and not a sprint. The pharmacological reason is the same as it is for Prozac. The therapeutic effect of Zoloft relies on receptor adaptivity and neuroplasticity. To prevent patients from getting frustrated and stopping the medication too early, I set expectations from the onset and explain the mechanism of action and how SSRIs have to be given time because they are changing the way the brain manages serotonin, not providing an external substance that magically improves mood.
When patients are looking to get off Zoloft, either due to completion of treatment or to trial another agent, tapering is required to reduce discontinuation effects. Tapering is variable and depends on the patient, the reason, and many other factors, but can usually be accomplished in one or two weeks. If we are stopping due to treatment completion, I tell patients from the onset I usually like to see symptom remission for one year before de-escalation is considered. I educate Zoloft is not a lifelong treatment and the medication offers a lot of flexibility.
While Zoloft’s half life is shorter than Prozac, it is long enough where patients are unaffected if they miss a couple doses. It also poses much less problem with discontinuation effects than agents with a shorter half life such as Paxil.
Below are some pearls about why I find Zoloft so useful:
- I like Zoloft in patients with heart disease. There is a lot of research to supper this and pharmacologically, it has minimal inhibition of hERG potassium channels. Studies have shown little to no risk of QT prolongation (delaying cardiac depolarization) as a result. Zoloft also has lower risk of electrolyte disturbances and interactions that can also attribute to arrhythmias (it is still a good idea to monitor sodium in at-risk populations).
- Zoloft has minimal anticholinergic activity, does not stimulate alpha receptors, and has fewer drug interactions (especially when dosed less than 150 mg daily). This is why I prefer it in geriatric patients, as I am always concerned for falls or polypharmacy. I’ve discussed before why tricyclic antidepressants (TCAs) fell out of favor to SSRIs and Zoloft is a good representation of that. TCAs have a much lower therapeutic index and have all of the traits mentioned here. Additionally, Zoloft has minimal H1 receptor activity, especially compared to TCAs, making it less likely to cause sedation or weight gain.
- Zoloft is my antidepressant of choice in pregnant patients. While Class C, like all SSRIs (except Paxil, which should only be used in women of child bearing age with extreme caution), Zoloft has been evaluated in large cohort and registry studies showing no consistent evidence of increased risk of major congenital malformations, particularly no strong association with cardiac defects. The medication has lower placental passage than Prozac or Celexa, meaning less fetal exposure. There is also minimal transfer in breast milk because it is highly protein bound, has a shorter half life than a medication like Prozac, and has low oral bioavailability in infants.
- Zoloft is considered to pose the lowest seizure risk of all the SSRIs, making it the medication of choice in patients with a history of epilepsy. This is due to many factors I have already mentioned, in addition to having clean receptor binding and less neuronal excitement. Research in stroke and traumatic brain injury (TBI) patients has shown Zoloft does not worsen seizure control.
- Zoloft has a wide dosing range that provides flexibility. My goal for every patient is to use the lowest effective dose with as few medications as possible. Zoloft gives the option for several adjustments where the dose can be tailored specifically to the patient’s needs.
In overdose, sole ingestions of Zoloft are the least likely of any SSRI to cause life-threatening toxicity. I have managed hundreds of Zoloft overdoses and I cannot recall a single case that developed seizures or arrhythmias as a result of Zoloft. The majority of patients did well with only mild toxic effects and many could be cleared for behavioral health placement as long as asymptomatic for a six hour period. This was an exposure I would caution the administration of activated charcoal was not worth the risk, as significant effects were not expected and I did not want a patient to aspirate on charcoal (from vomiting) when there was an extremely low risk their status was going to change to life-threatening. Management in the emergency department was straight forward, symptomatic and supportive, checking labs and EKG as a precaution and to call the poison center back with any significant problems, as these were always due to an unknown co-ingestion.
Providers in the emergency department should always order serum APAP, ASA, and ETOH levels on intentional overdoses, because it was these substances that could cause far more problems than Zoloft. I understand the hospital thinks the poison center is hyper fixated on these, especially acetaminophen, because we are. Acetaminophen toxicity is something that can be significantly delayed and we have the power to stop it without consequence if we know about it. Urine drug screens in the ER, are unreliable, and of minimal benefit in an acute overdose. Urine drug screens in the ER are rapid immunoassay screens, not gas chromatography–mass spectrometry or liquid chromatography–mass spectrometry, which are much more reliable, but also take much longer to get back.
Millions of patients are maintained on Zoloft and do great. Unfortunately, the majority of patients I see, are not ones I can just start Zoloft and have control over the mood symptoms. Zoloft is typically initiated in primary care settings and if the patient is coming to see me, Zoloft is not adequately controlling their symptoms or they have trialed and failed Zoloft.
If a patient comes to me on Zoloft, it is a medication I will try to keep around if possible. I consider Zoloft (and Lexapro) first-line among SSRIs and feel its efficacy, tolerability, and diversity make it a key component to treating a patient’s mood symptoms. If the patient comes to me looking for a change, I will take them off it, as I always tell patients, they know their brain, and if they are not happy, I am not happy. If a patient tells me they do not want to take Zoloft, I am not going to prescribe Zoloft.
A key component of fostering a healthy therapeutic alliance with a patient is developing mutual trust. I tell patients, if they do not trust me, nothing I do is going to be effective. That is why I engage patients in mutual decision making and I will assess and diagnose, but when it comes to formulating a treatment plan, I will only proceed as they are comfortable. I will obviously educate and offer expert guidance, but I do so in a way that is flexible and sees the patient in a way that embraces their humanity and unique characteristics. When practicing medicine, it is essential we offer evidence-based care, but evidence cannot be our only guide. We must listen to the patient and consider the way they feel because everyone’s experience is different and just because something is rooted in evidence, does not mean it replaces the patient’s experience.
Back to my original point, if a patient is on Zoloft, but still having bothersome mood symptoms, I start with reviewing the diagnosis. It is not uncommon to see a patient who carries a diagnosis of major depressive disorder and is prescribed Zoloft, but once I start interviewing the patient, I uncover periods of hypomania (or in some cases mania). Changing a diagnosis from unipolar depression to bipolar disorder is not something I take likely and must be proven without a reasonable doubt. It is through thorough interviewing, reliable screening instruments, and collateral information (through records or a present third party), that must be considered before a diagnosis is changed. If the diagnosis is changed from MDD, I usually do not start by tapering Zoloft. I start by initiating a mood stabilizer and reevaluating once it is therapeutic.
It is not always a case of a patient being treated for MDD when they are actually suffering from bipolar depression. Sometimes patients come to me who have been stable on Zoloft for a lengthy period of time but something situational has happened that has caused a problem. Sometimes there is a comorbid diagnosis that has not been adequately addressed. Sometimes there are medical etiologies, such as thyroid dysfunction or Vitamin D deficiency, that has negatively impacted mood.
I have had patients come in and request genetic testing, looking for alternatives from Zoloft. Again, if the patient wants off Zoloft, I will not go against the patient’s wishes. But I do want to briefly discuss genetic testing. Genetic testing in its current form is a useful tool that shows how a person’s body metabolizes psychopharmacological agents. The way it is marketed (all over my social media feeds), is that it is the solution to the patient’s symptoms. The results are neatly organized like a stoplight where it looks on first glance like a road map to mental wellness. That is not true and all of the research I have read to date is also uncertain.
I explain to patients genetic testing can provide useful information with how their body metabolizes drugs, but it will not provide information on efficacy. I will not take a patient off a safe, tolerable, and affordable medication for one that is unsafe, with many side effects, that can be more expensive, based on current genetic testing. For example, I am not going to use a TCA or MAOI just because it is in the “green” portion of a genetic test. All the genetic testing tells us is we may need a lower or higher dose. And sometimes, even that is not necessarily true.
There are a multitude of factors that determine the next step for a patient who presents on a therapeutic dose of Zoloft. Factors such as diagnosis, severity of symptoms, length of time on Zoloft, and past trials all must be considered.
Limiting polypharmacy is something I monitor vigilantly. I emphasize to patients, I am not a “pill pusher” and I am never going to be a provider who just adds and adds to a medication regimen. Not only is this not good for the patient, it is incredibly frustrating for all parties. During my time at poison center, I managed so many medication errors made at home, where patients were on medications to treat side effects from other medications. So when I get a patient on Zoloft, we look at what is going on and determine if symptoms can be addressed by adjusting the dose and explore non-pharmacological interventions for augmentation with psychotherapy.
Every person who walks through my office door knows, everyone is going to get a referral for psychotherapy unless they are already established with a therapist. Every treatment plan is unique but there is not a single person who would not benefit from therapy. The evidence is clear, psychotherapy is effective and many mood disorders can be adequately treated with routine therapy appointments. We see the best results when pharmacological and non-pharmacological interventions are combined to treat symptoms.
I see a lot of patients who are reluctant to pursue therapy. From past bad experiences to some people holding strong to the belief, therapy is just “not for them.” I tell patients to approach therapy as one hour all to themselves, they can use completely to their benefit. I educate reluctant patients they do not have to start with the darkest and hardest times of their life. That can only be done once a therapeutic alliance, rooted in trust, has been established. I encourage patients to start with day-to-day stressors or aggravations and keep an open mind, allowing for a trained professional, who is an objective third party, trained to help, to guide them.
In addition to psychotherapy augmentation, Zoloft’s diversity allows for it to be paired with other psychopharmacological agents to target residual symptoms. Agents like Wellbutrin (low energy), Trazodone (insomnia), and Buspirone (residual anxiety) can safely be used with Zoloft. In more severe cases of depression, OCD, anxiety, or PTSD, low-dose second-generation antipsychotics (like Abilify) are options to augment with Zoloft. Sometimes even if a patient is not bipolar, I will use Lamictal with Zoloft, especially if there is a lot of mood lability or irritability present. Pharmacological augmentation can be complex and always involves thorough evaluation before it is initiated. As stated, no one likes polypharmacy and it should only be initiated following patient-specific risk versus reward evaluation.
In conclusion, Zoloft plays an integral role in psychiatry and is widely used today. I consider it first-line for the conditions it is FDA-approved to treat and will continue to appreciate it as such. The best medications are the ones that are safe, tolerable, carry few drug interactions, and of course effective for the conditions they treat. Zoloft checks all of these boxes and is also affordable and widely available, regardless of insurance plan. Every patient is different and if Zoloft didn’t work for you, all hope is not lost. There are plenty of agents that can be effective and if Zoloft was not the right drug for you, discuss these concerns with your provider.
This post was written by Richard Gray, PMHNP-BC. The above information is for educational/entertainment purposes and is not intended to be treated as medical advice. If you have questions about a medication you are taking, discuss these questions with your medical provider