Many people are taking antidepressants to treat major depression or one of the many other conditions (i.e. anxiety, PTSD, OCD) for which they are prescribed. Antidepressants are clinically effective based on scientific research, which is why they are accepted as being first-line treatment options for depression. For certain people, taking antidepressants have improved their life to a significant extent.

Those that were previously crippled with overwhelming anxiety and/or hopelessness are now not only able to function, but are able to thrive. A major problem occurs though when someone who had been relying on an antidepressant to help them function suddenly realizes that their medication no longer works. A person may experience feelings of panic, returning sadness, and unwanted anxiety.

Why do antidepressants stop working? Tolerance.

Most medical professionals claim to not know why antidepressants stop working, even some psychiatrists. They claim that there are unknown reasons why antidepressants stop working for some and that it must be a result of “bad luck” or “individual differences.” While we know that antidepressants may work for a longer period of time in certain individuals, it is likely that they have diminishing returns over time – this applies to nearly every drug.

In reality it is relatively easy to figure out why antidepressants stop working. They stop working because a person builds up “tolerance.” In other words, your nervous system and brain become tolerant to the effects of the chemical that you have ingested over an extended period of time. Though the drug may work great for the first few months, eventually the drug will have rewired your brain functioning.

Specific reasons why antidepressants stop working

The most obvious reason that these medications stop working is that your nervous system becomes tolerant to their effects. This leads to a diminishing effect over time, thus requires either more of the drug, or a period of time off the drug for future benefit.

  1. Tolerance: This is the number one reason why your antidepressant medication may have “pooped out” or suddenly stopped working out of the blue. You may have been doing great on the medication, but seemingly out of nowhere your depression suddenly returns. When tolerance is established, not only could your original depression return, but the antidepressant side effects may become more prominent.
  2. Brain changes: There is evidence that taking an antidepressant is capable of changing the way your brain works within 3 hours of taking it. That’s right, the first dose of the antidepressant that you take is already rewiring your brain and making profound changes. Over time, the antidepressant medication has created so many changes, that your brain functioning becomes different, and eventually it stops working.
    • Activation: There may be changes in what parts of your brain are activated and how your brain functions compared to how it functioned prior to you taking the antidepressant. Due to the fact that most doctors will not bother to look at activation changes, you won’t really know what is different, but you can bet that the functioning of certain regions has changed.
    • Brain waves: There is a very good chance that your brain waves have also changed as a result of differing levels of neurotransmitters as well as changes in activation. You may have more slow wave activity in certain regions that require faster wave activity and vice versa. These brain wave alterations may have been influenced by the drug.
    • Neurotransmission: The levels of various neurotransmitters become altered over time when an antidepressant is used. Let’s say you’re taking a medication that’s mechanism of action involves inhibiting the reuptake of serotonin. Over time, your serotonergic functioning and serotonin levels become altered (possibly depleted) because extra serotonin is being used up. This is why the medication may stop working; it no longer has the fresh supply of serotonin like when you first started the drug.
  3. Adrenal fatigue: Some antidepressants (e.g. Paxil) are thought to essentially mine the adrenal glands over time. In other words, due to the potency of some SSRIs and the increase in serotonin, the body responds by increasing the amount of adrenaline secreted. Over time, the adrenals essentially burn out, and the beneficial effects of the drug wear off. When a person stops taking the medication, they may experience significant levels of fatigue as a result of the adrenal burn out. It will take time for the adrenals to recover if in fact the medication you were on resulted in adrenal depletion.
  4. Hormonal changes: It is thought that antidepressants can change a person’s level of hormones. Although the specific hormones that change may differ based on the individual and/or medication, some speculate that cortisol levels may increase throughout treatment. In any regard, some people end up with altered hormonal functioning while on antidepressants, which may influence the reduction in efficacy over time.
  5. Nervous system changes: There are possibly other changes that antidepressants make to our central nervous system. While we do know the mechanism of action behind the medications, we do not know all the specific changes that occur within the nervous system throughout treatment. Any drug is likely to alter homeostatic functioning over time and antidepressants do this to a significant extent, resulting in withdrawal symptoms long after a person has quit taking their medication.

Solutions: How to Make Antidepressants Work Again

First off if you are depressed, it is important to realize that while you may be depressed, antidepressants are not generally a great long term solution. Sure they may work for years in some people, but eventually a person is going to build up tolerance and need to either: increase the dosage OR withdraw from the medication to allow their body to recover.

Most people want the quick fix, so they increase the dosage. While there is nothing wrong with increasing the dosage, it doesn’t always work and/or may result in significantly more side effects. There are ways to make antidepressants work again, but you must be 100% sure that you want to take medication to treat your depression.

1. Increase dosage

This is the most obvious way to make an antidepressant work again. Let’s say you started at 10 mg of Lexapro and it stopped working after 6 months. The logical thing to do from the doctor’s perspective is to increase the dosage to either 15 mg or 20 mg. If you want to get the most benefit from an antidepressant, you should always be taking the lowest possible dose, and titrating up as slow as possible.

If you increase the dosage too much, the serotonin reuptake may be initially too powerful and may not result in the effects that you want. Titrate up to the next available dose and if that doesn’t work, then try an increment of another 5 mg up to 20 mg. There is no guarantee that a dosage increase will work, but there is a good chance that for most people, they had just become tolerant to the dosage that they were on.

Over time, the brain’s natural supply of serotonin and the influence of the medication has made significant changes. In order to bring back the initial antidepressant “spark” of efficacy, a dosage increase will likely be warranted. Like any strategy though, there are both pros and cons associated with merely upping the dose. A major “pro” is that it may work immediately, but a major “con” is that withdrawal will be significantly more difficult if you do eventually quit.

  • Pros: May work immediately, antidepressant relief, simple solution
  • Cons: Side effects, difficult withdrawal (if you ever want to quit), diminishing returns, may not work

2. Unrelated class of antidepressant

Since most antidepressants that demonstrate clinical efficacy in studies are serotonergic in mechanism of action, trying another serotonergic medication is less likely to be effective. Sure it may help mitigate the effects of low serotonin related to coming off of the medication that stopped working, but it will merely act as a patch for the low serotonin. If you give your brain and nervous system enough time to withdraw from the medication that stopped working, your serotonin levels will reset back to homeostasis.

Unfortunately this takes time (sometimes a really long time) and people with severe depression generally demand immediate relief. They can get immediate relief sometimes by switching to a completely unrelated class of medication. In the meantime, this will allow the depleted serotonin from the first medication to rebuild themselves. Let’s say now a person takes Wellbutrin which solely affects norepinephrine and dopamine – and it works.

Now the person can get relief from their depression, and not worry about further depleting serotonin. Of course they will face the dilemma of low norepinephrine when they quit Wellbutrin, but then essentially they maybe could switch back to their original serotonergic medication once they develop tolerance to the Wellbutrin. This may sound a lot like an addict replacing one drug with another, and the concept is somewhat similar, except in this case it is more consciously calculated.

Keep in mind that I am in no way suggesting that everyone is going to respond to a non-serotonergic class of medication. In fact, many people may get poor relief from atypical antidepressants, but some may find these other classes effective. One such example for the future will be ALKS 5461, which sounds promising.

  • Pros: New class may work well, allows serotonin levels to rebuild
  • Cons: New class may be ineffective, neurotransmitter chaos

3. Withdrawal / Drug-Free Period

The most difficult option to pursue on this list is that of going through complete withdrawal from the medication that stopped working and having an extended drug-free period. This would involve staying off of the medication for at least as long as the period for which you took it. You would want to work with your doctor and conduct a gradual taper off of your medication, and then do your best to function without any medication.

People that are pursuing this option will want to optimize their dietary intake, exercise habits, and stay as busy as possible. For those with serious depression, making it through an extended period without medication can be pure hell. However, on the flipside of the coin, assuming no medication that the person tries in the future works, they may end up feeling even more depressed than they would’ve had they just withdrawn.

Trying medication after medication with no break is like playing neurotransmitter roulette with your brain. Things are being altered, and you get thrown on another medication until something provides relief. Unfortunately in many cases nothing does provide relief and you continue trying medications that don’t really work. By taking an extended drug-free period, you allow your nervous system to heal and your neurotransmitter levels to rebound.

This strategy is akin to an alcoholic taking a break from drinking to lower their tolerance. By going for a significant amount of time without the medication, you are essentially resetting your functioning back to homeostasis or “pre-antidepressant.” As you fully heal, you will be able to go back on the same drug and should theoretically experience the same relief that was originally obtained.

  • Pros: Can reset the brain and nervous system back to homeostasis
  • Cons: Can take a long time, people underestimate healing time (and wonder why it doesn’t work), no other drugs can be taken during this time

4. Augmentation / combination treatments

For many people, an antidepressant medication stops working and their psychiatrist “adds” something to their treatment. Adding another medication is known as a “combination” treatment or antidepressant augmentation strategy. Essentially what is happening at this stage of the game is the person whose medication stopped working is now staying on their current medication because coming off of it would lead to further depression from low serotonin.

Additionally staying on their current medication will still work as a patch for the serotonin system to keep it running as it has been. The new medication will likely work on some other neurotransmitter in attempt to alleviate the depression. For many people this works initially because the new drug is essentially mining a different neurotransmitter.

Eventually the combination treatment may wear off and a third, fourth, or possibly fifth medication may get thrown into the psychotropic prescription arsenal. At this point, the person is likely overmedicated, but without their medications, they cannot function. The major problem though is that the person may not be able to function very well while on the vast number of medications.

Discontinuing multiple medications will be an even more difficult hell than coming off of just one. This is why withdrawal and a “break” earlier may have been a favorable strategy to experiencing absolute neurotransmitter chaos as a result of withdrawing from multiple medications. Like all strategies, even combination treatments have a shelf-life of efficacy before they stop working and/or doses need to be increased.

  • Pros: May work well initially
  • Cons: Creates further neurotransmitter chaos, most difficult withdrawal, extreme side effects

5. Antidepressant roulette

When I’m saying “antidepressant roulette” here I’m referring to a psychiatrist essentially testing you on all other medications in the same class, and then if those don’t work, trying a bunch of other medications. While this strategy could certainly fall under the headliner of trying “unrelated antidepressants,” in many cases psychiatrists will first try drugs related to the neurotransmitter that was targeted by the first medication.

This strategy may be temporarily helpful for some, because they may notice that a new drug provides a little bit of help based on a differing mechanism of action. In other cases, switching to a drug like Prozac may mitigate the transitional effects of the first medication and may in fact help make a person numb to their depression. Even drugs within the same class work differently, so therefore a new drug could work – this is what your psychiatrist is hoping.

The only problem with this strategy is that for many people, drugs with the same classification are not going to provide any relief. In the best case scenario they will provide a little relief, while in most cases they may not change anything. Sure they will help keep serotonin levels up to prevent a crash you’d experience during withdrawal, but they will not generally provide the relief you are seeking.

  • Pros: May be helpful, may act as a “patch” for serotonergic systems
  • Cons: No relief, may feel even worse

6. Psychotropic roulette

Lastly, a psychiatrist will likely engage in psychotropic roulette. If nothing is working, psychotropic substances will be thrown at you, some of which will be relatively potent (e.g. antipsychotics). Ultimately it is up to you to decide what you take and what you will not take. Personally, I would never take an antipsychotic medication due to the significant health risks and dangerous side effects.

In any regard, you won’t know what you’re going to get because each psychiatrist will handle things differently. One may want to try a mood stabilizer, another an antipsychotic, and another may be interested in trying a new antidepressant with an adjunct of T3 thyroid hormone. At this point it is neurochemical chaos in your brain and your nervous system has become extremely fragile.

You can only hope that something will eventually provide relief, but something that does may elicit unwanted side effects. Had you conducted a gradual taper off of your initial antidepressant that stopped working, you may be ahead of the game. But at this point you are so far deep in neurochemical warfare, that it’s difficult to even make decisions – so you just follow recommendations from your psychiatrist and pray.

  • Pros: Something usually will help
  • Cons: May not work, side effects may be awful

Which solution / strategy is the best?

There is no “best” option as there are benefits and drawbacks associated with each one. For most people with serious depression, coming off of a medication is tough to do because people believe that there will always be some sort of psychotropic relief available. In many cases of “refractory” depression, medication fails to provide benefit. In some of these cases, a person had initially found medication to be helpful, but then it stopped working and post-first-medication, nothing worked.

In order to really allow your nervous system / genetic homeostasis to reset itself, you likely need to spend a significant portion of time off of medication. For people with major depression, this is a counterintuitive option and one that may not be smart for everyone based on the degree of difficulty. However, assuming most other pharmaceutical treatment options don’t work, staying off of them and giving your body time to recover would put you in a more favorable position than creating further neurochemical chaos.

The body and brain are amazingly resilient and will recover to their pre-antidepressant state if given enough time to heal. However, the time they need to heal is highly individualized – therefore no specific timeline can be stated. It is ultimately up to you to choose your destiny and what you believe is the best option for dealing with your depression in the current moment. If given enough time to recover from the drug that “stopped working,” your tolerance will reset itself and eventually the initial dose will have the same effect that it had when it started working.