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How Long Does It Take For Zoloft To Work or “Kick In”?

Zoloft (Sertraline) is a selective-serotonin reuptake inhibitor (SSRI) prescribed for a variety of medical conditions, including: major depressive disorder, obsessive-compulsive disorder, panic disorder, and social anxiety disorder.  On occasion, Zoloft is even used off-label to help manage symptoms of premenstrual syndrome (PMS), body dysmorphic disorder, vascular headaches, and premature ejaculation.

Though the effectiveness of Zoloft is generally regarded as analogous to other antidepressant medications, one meta-analysis published in The Lancet (2009) reported that Zoloft may be superior to a majority of serotonergic antidepressants in terms of efficacy and tolerability among adults with major depressive disorder.  Because Zoloft is an effective treatment option for numerous conditions, and is sold for a low cost due to its generic status (approximately $1.50 for a monthly prescription) – it remains a popular medication.

In the event that you’ve been prescribed Zoloft to treat a medical condition, you might be wondering how long it’ll take for the medication to work or fully “kick in.”  In fact, you’ve probably been Googling how long it took for Zoloft to start working and are finding all sorts of mixed reviews: some suggesting that it works rapidly (immediately) and others noting that it takes weeks to reach full effect.

How long does it take for Zoloft to work – or “kick in”?

It depends on the user.  Although Zoloft starts working immediately in terms of exerting a neurophysiologic effect, it may take weeks for the medication to facilitate a desired or clinically relevant therapeutic effect.  That said, some users may notice that the medication starts working in a short amount of time (e.g. within hours or days of initiating treatment), whereas others may report that the medication takes several weeks to start working.

  1. Within days: Some individuals may notice Zoloft working within hours or days of administration.
  2. Within 8 weeks: A majority of individuals will notice Zoloft working within the first 8 weeks of administration.
  3. 8+ weeks: A smaller percentage of Zoloft users may require more than 8 weeks to notice an effect from the medication.

So which users are correct? Does the medication work right away – or will you need to take it for 4 to 6 weeks to derive therapeutic benefit?  The medication always starts “working” or modifying neurotransmitter concentrations within the brain on the very first day of administration.

In some cases, this will translate to a noticeable therapeutic effect within the first few hours or days of treatment and lead patients to report that the medication started working quickly.  That said, even though Zoloft is modifying neurochemistry on the first day of administration, not everyone consciously notices that they are under its influence.

Certain users may report zero noticeable effect from the drug early in treatment, whereas others may observe some side effects or modest changes in consciousness – but nothing that would be considered therapeutic.  With ongoing Zoloft treatment for 4 to 8 weeks, it is known that more substantial changes occur within the brain and central nervous system.

For example, within the first 4 to 8 weeks of treatment, 5-HT1A autoreceptors become downregulated, BDNF increases, and neurogenesis occurs within the hippocampal region of the brain.  A subset of individuals may exhibit these changes within shorter timeframes (e.g. 2 weeks) and report noticeable therapeutic benefit from Zoloft in ~2 weeks, whereas others may require a longer timeframe (e.g. 8 weeks) – leading to the conclusion that Zoloft starts working in around 8 weeks.

Assuming dosage is properly titrated, Zoloft should begin working for most recipients in under 8 weeks (some may notice a quicker effect than others).  Only a small percentage of users administering therapeutically-relevant doses of Zoloft will require more than 8 weeks to notice an effect.

Note: Not everyone derives therapeutic benefit from Zoloft.  Some users report that it makes them feel “numb” or even more depressed than before.  For this reason, it is important to avoid assuming that the medication “working” (modifying neurochemistry) always translates to a therapeutic or desired response.

Why Zoloft might work immediately (Possible reasons)

Included below is a list of explanations as to why Zoloft may start working immediately (within the first day or week of treatment).  Possible reasons as to why Zoloft may work much quicker than expected include: the placebo response; immediate neurochemical action (particularly in serotonin systems); and rapid alteration of neural connectivity. Keep in mind that there may be other reasons as to why Zoloft takes immediate effect besides the few listed below.

1. Placebo effect on Zoloft?

In the event that someone derives immediate therapeutic benefit from Zoloft, there’s a chance that a portion of this benefit may be attributable to the influence of a placebo effect.  The placebo effect refers to a substantial shift in neurophysiology solely as a result of believing that the medication will provide relief and/or alleviate symptoms.

In other words, if you believe that Zoloft could kick in immediately (prior to your treatment), this may yield a placebo antidepressant response, perhaps facilitating therapeutic benefit within hours of treatment initiation.  It is important to underscore though, that in persons who respond immediately to Zoloft – the placebo effect may play vary in terms of its impact.

Some immediate responders to Zoloft may be influenced entirely by the placebo effect, whereas others may respond immediately without any impact of the placebo effect.  Another portion of individuals may respond rapidly to Zoloft with some influence from a placebo response – and some influence of the medication’s action (each of varying degrees).

2. Zoloft’s immediate neurochemical action

Research suggests that Zoloft starts working in terms of its action upon neurochemical targets – almost immediately.  In other words, within an hour or two of taking Zoloft, the medication is modifying neurotransmitter levels throughout the brain, as well as receptor sites.  Zoloft functions primarily by inhibiting the reuptake of serotonin, but to a lesser extent (~100-fold), it interacts with the dopamine transporter and sigma-1 receptor.

Within a few hours of ingesting Zoloft, concentrations of extracellular serotonin will be noticeably increased – compared to pre-treatment.  Increased extracellular serotonin leads to greater serotonin signaling throughout the brain, which might explain rapid responses to the medication.  It is known that increased serotonin signaling alone can enhance mood, reduce anxiety, and mitigate obsessive thinking.

3. Zoloft alters neural connectivity within hours

Researchers have conducted studies in which neuroimaging scans (e.g. MRI) were used to examine neural connectivity among recipients of SSRIs.  It was discovered that recipients of SSRI medications exhibited significantly altered neural connectivity in under 3 hours post-SSRI administration.  This means that when you take Zoloft, it’s probably rewiring or rerouting neural connections within your brain in a relatively short duration.

Considering the rapidly altered neural connectivity arising from Zoloft administration, it’s possible that this might explain – or contribute to rapid responses to treatment.  Perhaps the altered neural connectivity stemming from Zoloft would be more significant in SSRI-naïve patients than persons transitioning to Zoloft from another SSRI medication.  Why? Because similar neural alterations might’ve occurred and/or lingered from previous SSRI use.

Why Zoloft might take a longer time to start working (Possible reasons)

If Zoloft doesn’t work as quick as you were expecting, below are some potential reasons as to why it might take a longer duration to “kick in.”  Possible reasons as to why Zoloft may take a while to fully alleviate your symptoms include: adaptations that require weeks to occur (e.g. downregulation of 5-HT1A receptors and neuroplastic changes) and/or dosage adjustments (e.g. titrating the dosage upwards).

1. Zoloft downregulates 5-HT1A receptors

For some individuals, it is believed that 5-HT1A receptor downregulation must occur for Zoloft to “work” or exert maximal therapeutic effect.  Though Zoloft manages to inhibit serotonin reuptake on the first day of treatment, reuptake inhibition doesn’t lead to 5-HT1A receptor downregulation until several weeks have passed.

The reason 5-HT1A receptor downregulation won’t occur immediately is because downregulation of 5-HT1A receptors is mediated by gene signaling.  Inhibition of serotonin reuptake yields increased extracellular serotonin concentrations, which in turn, stimulates 5-HT1A receptors.

When 5-HT1A receptors are stimulated, firing rates of serotonergic neurons decrease or become inhibited.  However, if 5-HT1A receptors are stimulated over a period of weeks, genes will signal to 5-HT1A receptors to downregulate (or decrease in number).

After 5-HT1A downregulation occurs, serotonergic neurons become disinhibited or increase in firing rate – stimulating postsynaptic receptors with a greater concentration of serotonin, leading users of the medication to perceive it as finally working.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/7972628

2. Zoloft induces neuroplastic changes

In addition to 5-HT1A receptor downregulation requiring several weeks, it may take several weeks of Zoloft treatment for the medication to induce therapeutic neuroplastic changes, namely: BDNF upregulation and hippocampal neurogenesis.  While it is understood that connectivity changes occur within hours of Zoloft administration, significant increases in BDNF (brain-derived neurotrophic factor) may take weeks.

After several weeks of treatment, Zoloft will have increased BDNF concentrations significantly enough to induce hippocampal neurogenesis – or the growth of new neurons in the hippocampus of the brain.  Because many neuropsychiatric conditions (including major depressive disorder) are associated with low BDNF levels and hippocampal dysfunction, perhaps enhanced hippocampal functioning following several weeks of treatment with Zoloft is what leads users to conclude that the medication has finally started working.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/21483429

3. Zoloft dosage adjustments

The dosage of Zoloft that’s administered will determine the potency of its neurochemical action.  Someone using a relatively low dose of Zoloft (e.g. 25 mg per day) will undergo less substantial neurophysiologic modulation than someone using a high dose (e.g. 200 mg per day).

If you start treatment with a very low dose, there’s a chance that the dose may not be high enough to modulate neurochemistry adequately to facilitate therapeutic benefit – or for you to notice that the medication is “working.”  As a result, your medical doctor or psychiatrist may suggest titrating the dosage upwards.  For example, you may increase your dose from 25 mg per day to 50 mg per day – or double your dose from 50 mg per day to 100 mg per day – after several weeks of treatment.

Perhaps after this titration or dosage increase, you’ll notice that the medication starts working.  In this case, you might’ve noticed the medication working much sooner if you would’ve started with a high dose (e.g. 100 mg per day).  Nevertheless, consider that suboptimal dosing early in treatment may have explained why Zoloft wasn’t working or took longer than expected to take effect.

Variables that influence the onset of Zoloft’s action

There are likely multiple variables that influence the length of time it takes for Zoloft to start working OR a person to notice Zoloft working.  Variables that likely influence time it takes for Zoloft to “work” include: Zoloft dosage; user genetics; prior medication use; concurrent substance use; preexisting medical conditions; and/or self-awareness.

A person who is very self-aware and medication-sensitive may notice Zoloft kicking in on the first day of treatment.  On the other hand, a person who starts treatment at too low of a dose and/or lacks self-awareness might not notice any effect until 4 to 8 weeks of treatment.

1. Starting Zoloft dose

The dose of Zoloft with which a person initiates his/her treatment may determine how long the medication takes to start working. In most cases, high doses of Zoloft are more likely to provide a more noticeable effect, and possibly be perceived as “working” sooner, than lower doses.

This is because high doses deliver a greater amount of the drug to the brain, allowing for more upfront and substantial neurochemical modulation than lower doses.  As a result, serotonergic signaling will be more pronounced in high dose users – and adaptations may occur at a faster rate (e.g. 5-HT1A downregulation and hippocampal neurogenesis) compared to lower dose users.

Moreover, some individuals may start with a subtherapeutic or low dose of Zoloft to see how their body responds.  These low initial starting doses might be insufficient to facilitate therapeutic relief.  As the dosage is titrated upwards over a period of several weeks into a therapeutic range, the medication may finally start “working” or reducing unwanted symptoms.

2. Zoloft user genetics

The gene expression of a Zoloft user might determine how long it takes for the medication to start working. It is understood that, following ingestion, Zoloft undergoes metabolism via many CYP450 isoenzymes, including: CYP2D6, CYP2C9, CYP2B6, CYP2C19 and CYP3A4.

Although genetically-mediated differences in isoenzyme expression aren’t thought to impact the pharmacokinetics of Zoloft, persons classified as poor CYP2C19 metabolizers exhibit 1.5-fold greater concentrations of Zoloft than normal metabolizers.  Data from in vitro studies indicate that decreased CYP2B6 function should increase Zoloft concentrations as well.

If you happen to exhibit abnormal CYP2C19 or CYP2B6 expression (as is determined by your genes), this could influence how your body metabolizes Zoloft – and ultimately how well it works and/or how quickly it takes effect.  Additionally, interindividual expression of genes (e.g. 5HTTPLR) that encode for various neurochemical targets of Zoloft might influence the rate at which it takes effect and/or its effectiveness.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/17146470/

3. Prior medication use (SSRI-naïve vs. non-naïve)

Anyone with a history of using serotonergic medications (or supplements, illicit drugs, etc.) that act similarly to Zoloft may respond quicker to its effect than someone without a history of using serotonergic agents. Assuming you recently used an SSRI medication for at least 8 weeks and transitioned to Zoloft without much time gap between treatments, you’ll likely already exhibit many of the neurochemical adaptations such as: 5-HT1A receptor downregulation and increased BDNF levels.

These preexisting neurochemical adaptations generally take up to 8 weeks for SSRI-naïve (i.e. persons without a history of SSRI use) to attain, and are understood to contribute to the medication’s therapeutic effect.  As a result of prior serotonergic medication use, you may respond to Zoloft relatively quickly due to preexisting 5-HT1A receptor downregulation and upregulated BDNF – coupled with the rapid neurochemical modulation exerted by Zoloft.

On the other hand, if you have no history of using serotonergic medications, it may take longer for you to notice an effect from Zoloft – as you won’t exhibit any preexisting neurophysiologic adaptations that require weeks to attain.  That said, it is important to underscore that not all users will require weeks to notice Zoloft working – all that may be needed for some individuals is a serotonin increase (without added 5-HT1A and BDNF modulation).

4. Concurrent substance use

Using any substances with Zoloft, including: prescription medications; illicit drugs; supplements; OTC meds – might influence the amount of time it takes for Zoloft to start working. It is known that using substances along with Zoloft could provoke pharmacokinetically-mediated or pharmacodynamically-mediated interactions.

In other words, substances used along with Zoloft might interact with its absorption, metabolism, distribution, and excretion – or perhaps with its effect exerted upon neurochemical targets.  Any co-administered substance that interacts with the same CYP450 isoenzymes as Zoloft, particularly CYP2C19 and/or CYP2B6 enzymes – might alter serum concentrations of the medication and affect how quickly it begins working.

Moreover, some co-administered substances might bolster the neurochemical effects (e.g. serotonergic modulation) exerted by Zoloft within the brain.  If a concurrently-administered agent augments the neurochemical effect of Zoloft within the brain – this may result in a faster onset of action.  Oppositely, if a concurrently-administered agent counteracts certain neurochemical actions of Zoloft – it may result in a delayed onset of action, or possibly interfere with its efficacy.

5. Preexisting medical conditions

Preexisting medical conditions may influence how quickly you respond to Zoloft. For example, it is known that persons with bipolar disorder are at increased risk of experiencing a manic (BP1) or hypomanic (BP2) switch in the early stages of SSRI treatment as a result of the serotonergic modulation provided by the medication.

Opposite of persons with bipolar disorder, patients with brain damage or a neurodegenerative disorder (e.g. Alzheimer’s disease) may require more time than usual for the medication to provide a noticeable or therapeutic effect.  Additionally, medical conditions such as: hepatic and/or renal impairment might interfere with proper metabolism and/or clearance of Zoloft – possibly affecting how much time is needed for the medication to take effect.

6. Zoloft “user-specific” factors

There are some user-specific factors that may influence how long it takes Zoloft to begin working. The details associated with Zoloft administration such as: the time of day at which Zoloft is administered, as well as whether the medication is taken with food versus on an empty stomach – could affect how rapidly it start working. Furthermore, the self-awareness of a user may influence how quickly he/she notices the effect of Zoloft.

Administration details: It’s possible that there may be circadian rhythm interactions with Zoloft such that the time of day at which it is administered might influence its efficacy and/or onset of action.  In other words, the “chronopharmacodynamics” of Zoloft may differ with morning administration compared to afternoon or nighttime administration.

Assuming your circadian rhythm is relatively normal, it may be best to administer Zoloft first thing in the morning.  In the morning, the body is typically most insulin sensitive and might be best equipped to ingest foods and metabolize substances – compared to later in the day.  That said, some individuals may find the exact opposite: Zoloft works quicker if administered at night – or at equal speeds regardless of timing.

Whether Zoloft is administered with food or on an empty stomach might determine how well it works.  Some users may claim that Zoloft is more effective and kicks in quicker if administered on an empty stomach.  Others may report zero effect of food on the onset of therapeutic effect derived from Zoloft.

Self-awareness: Self-awareness does not influence how long it takes Zoloft to start working, but it might influence how long it takes you to notice its effect.  If you’re extremely self-aware, chances are good that you’ll notice Zoloft exerting some sort of an effect within the first couple days of treatment.

Though the drug may not be providing a therapeutic effect in the first couple days, self-aware individuals will notice that the drug is “working” or has taken effect.  Oppositely, if you have very low self-awareness or internal focus, it may take a much longer duration to notice any effect of Zoloft.

A person with extremely low self-awareness may require up to 8 weeks of treatment and significant dosage increases (from the starting dose) to notice any effect of the medication.  Regularly practicing medication or engaging in self-reflection may help increase self-awareness and aid in expediting the detection of the effect derived from Zoloft.

How long did Zoloft take to “kick in” for me?

Years ago when I was prescribed Zoloft by a psychiatrist, I initiated treatment at the lowest therapeutic dose (50 mg) and titrated upwards to higher doses (100 mg, then 150 mg).  Because I had severe anxiety plus depression, my psychiatrist recommended using Zoloft for at least 8 weeks to accurately assess its effect.

At the lowest dose (50 mg), Zoloft significantly worsened my anxiety and depression – plus I became agitated, angry, and couldn’t think my way out of a wet paper bag.  I continued the 8-week trial and ended up feeling depersonalized – plus substantially more anxious and depressed than before using Zoloft.

On the very first day of Zoloft treatment, I noticed a mild effect from the medication.  Within 3 days of treatment, this effect became more pronounced.  Zoloft significantly altered my thinking, perception, and caused severe brain fog – plus other unwanted side effects, all in less than 1 week of treatment.

Though technically my experience may have been a “nocebo response” – I’m very skeptical of a nocebo response considering we know that SSRIs like Zoloft act on neurochemical targets plus alter neural connectivity throughout the brain in less than 3 hours after administration.  In any regard, I continued the 8-week trial of Zoloft and felt totally miserable after week 8.

In summary, I definitely noticed the medication “working” within the first week of treatment, but it wasn’t providing any therapeutic effect – in fact, for me, the medication induced an antitherapeutic effect.  Eventually, I had to undergo Zoloft withdrawal (this really sucked) and wait up to ~16 days for all metabolites of Zoloft to leave my system.  Then, like a lab rat, I geared up for my next antidepressant trial.

How long did it take for Zoloft to work for you?

If you’ve used Zoloft, also known as sertraline, how long did it take for the medication to “work”?  More specifically, how long did it take for you to notice an effect of Zoloft – or that you were under the influence of a medication after starting treatment?  After initiating treatment, how long did it take for you to derive therapeutic benefit from Zoloft? (This is assuming you benefitted).

To help others better understand your experience with Zoloft – and its onset of action, provide details in your comment such as: your starting dose; whether you titrated the dosage upwards (or maintained); and whether you had a history of antidepressant use prior to taking Zoloft.  Be sure to also note things like: the specific condition for which you were using Zoloft; whether you have any preexisting medical conditions that might influence its effect (e.g. hepatic dysfunction); and/or whether you’re using any other substances (medications, supplements, etc.) along with Zoloft.

Consider mentioning the time of day at which you administered Zoloft – as well as whether you took it with food versus on an empty stomach.  Moreover, if you had to rate your self-awareness on a scale from 1 to 10 – what would you rate yourself (assuming “1” is least self-aware and “10” is most self-aware).

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{ 1 comment… add one }
  • Terry May 26, 2018, 9:59 pm

    I started taking Zoloft approximately five weeks ago. I had been on Paxil for many years before starting Zoloft. I am also taking Geodon twice daily. At first I experienced more anxiety for about three weeks. At three weeks all my anxiety seemed to disappear.

    That lasted about a week and then the anxiety came back and I found myself having to take Geodon sometimes three times a day. Since Geodon has a short half-life, I start to experience severe anxiety after about seven or eight hours which gets better about an hour after taking another Geodon.

    I’m only supposed to take Geodon twice a day and I had no trouble keeping to that schedule while on Paxil. I’m hoping the Zoloft kicks in within the next couple weeks to eliminate my anxiety or I am afraid I will be forced to go back to Paxil.

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