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Antidepressant Augmentation Strategies for Treatment-Resistant Depression

Antidepressant augmentation strategies are commonly reviewed when an individual is unresponsive to monotherapeutic treatment. In other words, people that try treatments by themselves such as: using an SSRI medication or going to cognitive behavioral therapy (CBT) may not have as great of a response as if the treatments were combined. In some cases, a person may respond pretty well to an antidepressant medication, but may find that it is not working as well as they expected. In this case, a psychiatrist may want to review some antidepressant augmentation strategies.

When I first visited my psychiatrist, he actually put me through the wringer of SSRIs, SNRIs, TCAs, and MAOIs before suggesting that I try augmenting my SSRI with a psychostimulant. In most cases with augmentation, a psychiatrist takes a proven treatment, and adds something to it in order to boost effectiveness. Common examples of augmentation include: cognitive behavioral therapy (CBT), other classes of antidepressants, psychostimulants, thyroid hormone, lithium, and atypical antipsychotics.

A particular technicality that should be noted is that “augmentation” means adding a medication (or treatment) that is not established as a primary antidepressant to enhance the effects of the first medication. The term “combination therapy” typically is used to describe to antidepressants being used together. However, for the sake of this article, I am going to include all strategies.

Antidepressant Augmentation Strategies for Treatment-Resistant Depression

Below I attempted to organize and list (with no regards to hieararchy) the most effective augmentation strategies for depression. Keep in mind that augmentation strategies are typically only utilized if the initial choice(s) of treatment have not been effective.

1. Cognitive Behavioral Therapy (CBT)

Perhaps the best way to augment the treatment of depression is to utilize cognitive behavioral therapy (CBT). This is a specific type of psychotherapy that has been proven to treat symptoms of depression as well as mainstream antidepressants. For some, CBT actually works better than an SSRI. The combination of CBT and an SSRI like Prozac has been shown to be the most effective at alleviating symptoms of depression when compared to either as a standalone treatment.

It has also been researched that CBT when used instead of medications worked as well as major antidepressants such as: Zoloft, Wellbutrin, and Effexor. Also when added to ongoing Celexa treatment, cognitive behavioral therapy had about the same chance at helping people as augmenting Wellbutrin with Celexa.

The great thing about CBT is that there aren’t any side effects from adding on an additional drug. For this reason, if you haven’t yet explored CBT, it would be the first line of adjunctive treatment to consider.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15315995

2. Thyroid hormone: T3 (Triiodothyronine)

Thyroid hormone, commonly referred to as “T3” is a well-established augmentation strategy for treating major depression. It could be especially effective in individuals who show some indication of thyroid function. This treatment strategy has been shown to be effective in a Star*D study – aimed at specifically study depression.

Despite the fact that many people do not want to be treated with thyroid hormone, the side effects may actually prove to be less bothersome than a more severe medication like an atypical antipsychotic. All that is required is that the “T3” levels reach therapeutic amounts in your body and most people end up noticing some relief from their depressive symptoms.

  • Source: http://www.currentpsychiatry.com/index.php?id=22661&tx_ttnews[tt_news]=176104
  • Source: http://jop.sagepub.com/content/20/3_suppl/11.short
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9629954

3. Lithium (Mood stabilizer)

Lithium is a naturally occurring element, but has been effective as a treatment option for bipolar disorder. It has also been effectively used to help in cases of bipolar depression. People that are experiencing depression as a result of their bipolar cycling (e.g. rapid or slow), will likely have better results with lithium for their treatment.

Augmentation of lithium can also be utilized in individuals that do not have bipolar disorder. The reason to use lithium for treatment resistant depression is primarily due to the fact that it can help stabilize mood. If you are significantly depressed, the thought is that lithium will help it return to some degree of normalcy. Other mood stabilizers have also shown promise, but lithium is the most documented.

The only major downfall associated with lithium augmentation is that it comes with need for blood work and potential long-term side effects. Tremors, unpleasant tastes, and excessive urination are all common side effects.

  • Source: http://europepmc.org/abstract/MED/12971013

4. Adderall (Psychostimulants)

Augmentation of Adderall or mixed amphetamine salts (dextro-amphetamine / levo-amphetamine) is a common strategy to help people with both attention-deficit disorder and depression. In some individuals, the symptoms of depression can be a result of an underlying attention-deficit disorder. In individuals with extreme fatigue, apathy, psychomotor retardation, and/or poor concentration, this may be an effective augmentation strategy. However, in people with high potential for addiction, this may be a substance to avoid.

When I was prescribed Adderall for treatment resistant depression, it actually ended up helping immediately. If someone needs immediate relief from feeling suicidal, this may be something to consider. In order to get a prescription for this medication, you must be able to prove that you either have: comorbid ADD, psychomotor retardation, a non-addictive personality, and/or not responded to other treatments.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9614599
  • Source: https://store.acponline.org/ebizatpro/images/ProductImages/books/sample%20chapters/PsychCh05.pdf

5. Modafinil (Eugeroics)

Vigilance promoting agents such as Provigil (Modafinil) have been utilized as an augmentation strategy to help with depression. One of the biggest benefits associated with this class of drugs is that they help alleviate symptoms of fatigue and sleepiness throughout the day. If depression is caused by a condition such as fibromyalgia or existing treatment is making a person tired, a eugeroic medication may be advised for augmentation.

Usually this is only prescribed for individuals that have a severe fatigue that accompanies their depression and/or is a side effect from their existing treatment. Some psychiatrists may actually favor this medication over psychostimulants because it has low abuse potential and is a Schedule IV drug. Others debate the long term safety of this medication and favor the use of the more studied psychostimulant class of medications.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/10847314

6. Buspirone & Anti-Anxiety (Anxiolytic)

Although the anxiolytic class of medications do not directly help depression, they may help in cases where a person’s anxiety is causing them to feel depressed. Certain individuals can actually end up depressed if they are unable to treat their underlying anxiety. In this case, the first line of treatment is typically something like Buspirone (Buspar).

Buspirone is an anti-anxiety drug that carries relatively few side effects compared to other anxiolytic medications such as benzodiazepines and sedative hypnotics. It should be understood that this class of medications should only be utilized in cases of comorbid anxiety and/or anxiety as a result of a medication. In some cases this class can serve as an effective augmentation.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9635547

7. Wellbutrin (Buproprion)

One common practice that’s considered pretty safe is adding Wellbutrin in conjunction with an SSRI for treatment. Some people don’t respond well to SSRI’s and/or may be off-put by some of the difficult side effects. Since SSRI’s primarily work by inhibiting the reuptake of serotonin in the brain, adding a non-SSRI antidepressant such as Wellbutrin can be effective.

It should be noted that it may be a good idea to first explore whether Wellbutrin could work on its own before keeping the SSRI as an augmentation. Similarly if you are already on Wellbutrin and are experiencing anxiety, your doctor may suggest augmentation of an SSRI medication like Prozac. Wellbutrin is a norepinephrine-dopamine reuptake inhibitor (NDRI) but it is considered to affect dopamine more than norepinephrine.

Since it doesn’t act on the same neurotransmitters as does SSRI’s it can be safely used as an augmentation strategy. In studies with Celexa, it was found that the Wellbutrin SR (sustained-release) actually was more effective than the standard version. It should be noted that despite the fact that this is among the most common augmentation strategies, there isn’t as much research to support this option as you’d think.

  • Source: http://www.nejm.org/doi/full/10.1056/nejmoa052964

8. Atypical antipsychotics

If my psychiatrist or doctor suggested this treatment option, I would probably close my eyes and run for the hills. Unless you are in absolutely dire straits or need to take an antipsychotic anyway, it would be best to stay off of one. Just look up the side effect profiles of these drugs, read about some experiences, and you should be scared enough. I have personally been on one for a week and it was one of the worst experiences of my life; never again.

The bottom line though is that these have proven to be an effective augmentation strategy to treat major depressive disorder. If you don’t really care about the side effects or can manage to put up with a lot of unwanted side effects, then these may be an option to consider. However, these should not be taken lightly as they are amongst the most powerful class of psychiatric medications on the market.

Atypical antipsychotics are the second generation of antipsychotic medications and are generally thought to be slightly better tolerated than older typical antipsychotics. If you have more insomnia-related symptoms medications such as quetiapine and olanzapine are more likely to be prescribed. If you have more difficulty with fatigue or psychomotor retardation, aripriprizole is likely a superior option. The atypical antipsychotic class when used as an augmentation strategy ends up being effective between 10% and 30% of the time.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19687129
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/17288688

Which augmentation strategy is best for your depression?

It totally depends on your symptoms and what your psychiatrist thinks. You should first get a proper psychiatric evaluation. If you are severely depressed, you should weigh the pros and cons of each option on this list before choosing a treatment. Some people like myself simply would never allow myself to be on lithium or take an antipsychotic. Others that may be less prone to side effects or that are able to put up with more may want to consider those options.

Although I am not a medical professional, my opinion is that obviously cognitive-behavioral therapy (CBT) should be considered before everything else. If that doesn’t work, I would probably try either psychostimulants or eugeroics. If you are addiction prone, those may not be the best options. Thyroid hormone and lithium are two well researched options if you aren’t responding well to other options. Due to their extreme side effect profiles, I think that antipsychotics should be used as an absolute last resort if absolutely nothing else helps.

  • Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958866/
  • Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2424118/

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{ 8 comments… add one }
  • Sasha Cherrington May 9, 2017, 1:07 pm

    Interesting facts. I am on Wellbutrin + Lithium. I also take Seroquel.

  • Nadine September 17, 2016, 8:38 pm

    I’ve heard good things about ketamine (not the street stuff) had some for a surgical procedure and was the best I felt in my life! There are clinics but costs and distance are prohibitive!

  • Robert May 23, 2016, 2:12 am

    I have taken Wellbutrin Buspirone, Addermeth, SSRI’s, Modafinil, Armodafinil, Remeron, Seroquel, L-Dopa, etc. in nearly every combination. NOTHING has ever helped my depression or anxiety. Until I got an abscessed tooth and received Tramodol. I was actually happy for 3 days!!! And no I have never been an opiate user I quit meth 5 years ago. I’m 45 and have been sad my entire life as it runs in my family. TRUTH is right on. Look up “Relmada’s d-methadone The Next Big Thing” on BioNap. There may be hope someday for those of us that are suffering.

  • Andrew December 7, 2015, 4:26 am

    The fact is “truth’s” comments come across as extreme and therefore sound irrational but the truth is, excuse the pun he is for many people like myself on the mark when it comes to treating severe depression with opioids. They work very well and in my case have been on them for many years after trying every SSRI, SNRI, and all the augmentation strategies listed in the above article including lithium, CBT, etc.

    Opioids I fortunately found by accident, literally and immediately obtained relief of my depression and anxiety. Having a wonderful enlightened doctor who would prescribe opioids was also a blessing for me. The side effects are minimal to none compared to SSRIs particularly except for constipation initially which completely went away for me after a few months and one does not need anything more powerful than morphine although I prefer fentanyl which for me is not in any respect dangerous regarding the potential for overdosing.

    It just is not possible as you will get sick and vomit long before any higher level is ingested that could cause a problem. To me it was a wonder drug but few can get it and many will unfortunately not get the same result as I have but those who do know what I mean. I worked in a high level management position and no one ever knew of my condition or use of the medication when taken responsibly. I hope this may help someone out there…just do your research as the evidence is there and has been proven effective for many severely depressed people. I am happily living proof of this fact.

  • Truth June 28, 2015, 2:25 am

    These things don’t work, the things that really work to bring any minimal relief against depression are all restricted or banned. the policy makers that set this policy never suffer and they do not care if they make it so someone suffering cannot get anything they want to try to bring minimal relief. Notice there’s nothing Opioidergic on this list so if you have a problem with the body’s opioid/endorphin pathways, you suffer till death and this is backed by deadly force…

    This is all fake, to lower dysphoria a person has to be given opioids or the partial opioid agonist buprenorphine, also things like mGlur5 antagonists… things like lithium and stimulants have no impact on dysphoria, nor does the typical “antidepressants” that these things are augmenting. The system is all fake & evil, it wants people to suffer for life with never any relief, because it ALWAYS offers ONLY medications that do not work and COINCIDENTALLY bans or restricts all meds that do work.

    And the people who make this policy exist are also people who never, ever suffer. They philosophically believe in authoritarianism. They have the belief that things should be controlled and that controlled should be backed by automatic weapons and deadly force, so there will never be any company making and selling meds that work, nor any doctor prescribing meds that work, because they will be either arrested at gunpoint, or shot dead as a result.

    • Scott September 22, 2015, 6:43 pm

      Bullsh**. When did anyone EVER say, “I tried Prozac, Wellbutrin, Lithium, Effexor, Elavil and Zoloft. They didn’t work. But once I got on heroin, I turned my life around.”

      • Xabit March 20, 2016, 10:46 pm

        I’d like to second this. I’ve suffered from depression and anxiety for several years. After surgery I was prescribed oxycodone which I found provided nothing other then a slight increase in mood. Depression is far too complicated to be attributed to simply one system within the brain. That’s why there are numerous antidepressants currently in the pipeline including triple reuptake inhibitors and NMDA antagonists just to name a few.

      • Tara June 1, 2016, 7:00 pm

        I’ve tried all the meds that you’ve mentioned. I am also on an opioid (methadone) for a neurological disorder. But the thing with opioids is that they tend to INCREASE depression. Then people treat the depression with more meds, which sometimes agitate the neurological system, and call for… guess what… more opioids which worsen depression…. sigh.

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