Antidepressants Not Working? Here’s What to Do Next

Antidepressant medications are an important component of therapy strategies for many people, helping to manage depression symptoms and improve overall well-being. However, not all medications work for every individual, and not everyone may experience the desired level of improvement from these drugs. If you find that your prescribed depression medications aren’t working or aren’t as effective as they once were, don’t worry. This article will discuss some of the most common and effective approaches to treating depression.

It’s Not Just You

Each year, depression affects over 14 million U.S. adults. While some people can achieve full remission from depression with the help of traditional treatments, this is not the case for everyone. About 30-40% of those 14 million diagnosed with major depressive disorder, despite adequate prescription medications and/or therapy, do not experience improvement in their symptoms. They develop treatment resistance also known as treatment refractory depression or TRD.

Treatment-resistant depression is defined as the failure to respond or achieve remission after two or more trials of antidepressant medication of adequate dose and duration. If antidepressants and talk therapy aren’t working for you, you’re not alone and it doesn’t mean you can’t feel better. There are many alternative and non-drug treatments available that can help.

Efficacy of Depression Medication

For individuals who have tried traditional treatments like SSRIs (Selective Serotonin Reuptake Inhibitors) without success, it’s important to know you’re not alone. The STAR*D Trial, a significant study in the field of depression research, highlighted that SSRIs only work for about 50% of people and commonly provide only a modest reduction in symptoms. [8]

Sometimes, antidepressants lose effectiveness over time. This is called breakthrough depression. While you may have found relief from depression symptoms with a certain antidepressant medication in the past, if your antidepressant isn’t working like it is supposed to, it’s important to reach out to a mental health professional.

Signs Your Antidepressant Medication Isn’t Working

If you believe your antidepressant medication is not working for you, speak up. It’s important to consult with a healthcare professional for a thorough evaluation of your symptoms, but here are some potential signs to be mindful of:

Persistent or worsening symptoms:

If your depression symptoms persist or intensify despite taking the prescribed medication for a significant period, it may indicate that the current medication is not adequately addressing your condition.

Lack of improvement in daily functioning:

If you notice little to no improvement in your ability to engage in daily activities, fulfill responsibilities, or enjoy previously pleasurable activities, it could suggest that the medication is not effectively managing your depression symptoms.

Continued sleep disturbances:

Difficulty falling asleep, staying asleep, or experiencing excessive sleepiness even after being on antidepressant medication may indicate a need for reassessment.

Emotional fluctuations:

Frequent mood swings, persistent irritability, or feelings of emptiness and hopelessness despite medication usage could suggest that the current treatment approach is not providing the desired emotional stability.

Persistent side effects:

While some side effects are common when starting antidepressant medication, if you are experiencing severe or persistent side effects that significantly impact your daily life, it’s essential to discuss this with your healthcare provider.

Suicidal thoughts or increased thoughts of self-harm:

If you notice an increase in suicidal thoughts or feelings of self-harm after starting medication, it is crucial to seek immediate medical attention.

Remember, everyone’s response to medication is unique, and it may take time to find the right treatment approach. Open and honest communication with your healthcare provider is essential to address any concerns, adjust medication if necessary, or explore alternative treatment options to optimize your mental health care.

Common Antidepressant Medications

Depression can be difficult to manage, and finding the right medications might take trial and error. Not every medication works the same for everyone or is equally effective for everyone, but the good news is research is ongoing, and there are several different medications currently available to treat depression.

While all antidepressants affect the brain, each type has different mechanisms of action, which means they target various neurotransmitters. Neurotransmitters serve as messengers that communicate between cells in the brain. These messengers, in turn, work to change brain chemistry, which reduces or relieves depression and regulates moods.

There are many different classes of antidepressant medications. The most common are selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), atypical antidepressants, serotonin modulators, tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).

Selective serotonin reuptake inhibitors (SSRIs):

SSRIs are the most commonly prescribed and are considered the first-line agents for treating depression and work to increase serotonin levels in the brain, helping to regulate mood and emotions. [10]

SSRIs include:

  • Prozac (fluoxetine)
  • Zoloft (sertraline)
  • Celexa (citalopram)
  • Lexapro (escitalopram)
  • Paxil (paroxetine)
  • Luvox (fluvoxamine)[10]

SSRIs are also used to treat a number of other types of mental illness including bipolar disorder, anxiety disorders, and mood disorders.

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

SNRIs are the next most commonly prescribed medications, and they target both serotonin and norepinephrine, providing a dual mechanism of action for managing depressive symptoms.

SNRIs include:

  • Effexor (venlafaxine)
  • Pristiq (desvenlafaxine)
  • Cymbalta (duloxetine)
  • Savella (milnacipran)
  • Fetzima (levomilnacipran)

Atypical Antidepressants:

Atypical antidepressants include medications that do not fit into the traditional classifications but can still be effective in treating depression and have several mechanisms of action. [10]

Atypical antidepressants include:

  • Wellbutrin (buproprion)
  • Remeron (mirtazapine)
  • Auvelity (dextromethorphan & bupropion)
  • Valdoxan (agomelatine) [10]

Bupropion takes about two weeks to see some improvement in symptoms and about four weeks to reach full efficacy. It has shown similar remission rates to SSRIs and has a median time to relapse of 44 weeks. [9]

Mirtazapine, unlike other antidepressants, reduces cortisol levels in the body. [9] Studies involving pharmaceutical administration for up to 40 weeks have provided long-term data on the effectiveness of mirtazapine, which show ongoing improvements in response rates and lower relapse rates compared to placebo. [9]

Tricyclic Antidepressants (TCAs):

Tricyclic antidepressants affect around five separate neurotransmitter pathways [6] and prevent the reabsorption of serotonin and norepinephrine neurotransmitters. Like other antidepressants, they affect the level of chemicals in the brain which regulate moods and emotions. [10]

Tricyclic antidepressants include:

  • Elavil (amitriptyline)
  • Anafranil (clomipramine)
  • Prudoxin (doxepin)
  • Tofranil (imipramine)
  • Surmontil (trimipramine)
  • Norpramin (desipramine)
  • Pamelor (nortriptyline)
  • Vivactil (protriptyline)
  • Ludiomil (maprotiline)
  • Asendin (amoxapine) [10]

While TCAs may work as well as SSRIs, they are known to cause more significant side effects due to anticholinergic activity, so because of this, they are not considered first-line treatment for depression. [6]

TCAs are also used off-label to help prevent migraine headaches, obsessive-compulsive disorder (OCD), insomnia, anxiety, and chronic pain. They are sometimes used as a second-line treatment for fibromyalgia. [6]

Monoamine Oxidase Inhibitors (MAOIs):

Monoamine oxidase inhibitors (MAOIs) are considered a separate class of antidepressants, and they are used to treat depression and nervous system disorders such as panic disorder and social phobia. [11]

MAOIs include:

  • Selegiline
  • Moclobemide
  • Tranylcypromine
  • Isocarboxazid
  • Phenelzine [10]

MAOIs have shown comparable effectiveness as tricyclic antidepressants [5]. However, they are typically only used when other medications have been unsuccessful [5,11] because they require several dietary restrictions due to their potentially harmful side effects and safety concerns for some people. [11]

Serotonin modulators:

Serotonin modulators are an alternative to SSRIs and SNRIs for adults experiencing major depressive disorder and have similar response rates as SSRIs and SNRIs. Serotonin modulator antidepressants act on the neurotransmitter serotonin in the brain to treat mental health disorders such as depression, anxiety, and obsessive-compulsive disorder.

These drugs work by either increasing or decreasing the serotonin activity in the brain, depending on the type of drug.

Serotonin modulator antidepressants include:

  • Serzone (nefazodone)
  • Desyrel, Oleptro (trazodone)
  • Vlibryd (vilazodone)
  • Trintellix (vortioxetine) [10]

Trintellix (vortioxetine) is a new antidepressant drug and treatment for major depressive disorder (MDD) in adults. [2] Trintellix is thought to increase the level of the neurotransmitter (brain chemical) serotonin but differs from other antidepressants in that it targets several serotonin receptors and inhibits serotonin reuptake. Clinical trials have shown vortioxetine provides greater symptom relief and longer symptom-free periods [1,2]

Alternative Depression Treatments

Alternative depression treatments offer individuals different approaches to managing depression symptoms compared to traditional oral antidepressant medication. These approaches provide individuals with a range of options to explore in their journey toward finding effective and personalized strategies for managing and alleviating symptoms of depression. Although they are typically not yet used as first-line treatment options, they can be just as or more effective as oral antidepressants.

Transcranial Magnetic Stimulation (TMS) Therapy:

Transcranial magnetic stimulation (TMS) is a non-invasive procedure that is approved to treat major depression disorder (MDD) and obsessive-compulsive disorder (OCD). [4] When traditional antidepressant medications fail to provide the desired relief, TMS therapy can be an effective alternative.

TMS therapy stimulates specific areas of the brain responsible for regulating mood. This non-invasive procedure has shown promising results, particularly for individuals who have not responded well to antidepressant medication. By targeting the underlying neural circuitry of depression, TMS therapy offers a unique approach to treatment. [4]

If you or someone you know is struggling with depression and antidepressant medications are not providing relief, contact Neuro Wellness Spa to learn about the potential benefits of Transcranial Magnetic Stimulation (TMS) treatment.

TMS has been proven effective for depression with minimal side effects. Our experienced team has treated 91,909 people with TMS, and 75% have achieved a statistically significant reduction in symptoms. Come experience our cutting-edge treatments and get the help you need today!

Holistic Treatments

In addition to these medical interventions, holistic methods can also play a key role in managing depression. Holistic approaches recognize the interconnectedness of the mind, body, and spirit and aim to address the underlying causes of depression rather than simply alleviating symptoms.

Some holistic techniques that may be beneficial include:


Engaging in talk therapy, such as cognitive-behavioral therapy (CBT), can help individuals develop coping strategies, challenge negative thought patterns, and improve emotional well-being. Psychotherapy is commonly the first treatment for mild to moderate major depressive disorder (MDD). [5]

Evidence has shown that two types of psychotherapy may be particularly helpful in depression treatment: cognitive-behavioral therapy (CBT) and interpersonal therapy (IPT). [5] Once individuals reach remission, CBT, psychoeducational intervention (PEI), and mindfulness-based cognitive therapy (MBCT) are suggested for maintaining and preventing depression.[5] Psychotherapy is also important in maintaining remission and preventing relapses. [5]

Exercise and Healthy Lifestyle Habits:

Regular physical activity is good for everyone, but evidence shows Engaging in activities such as walking, yoga, or jogging can help reduce symptoms of depression and promote overall well-being. [5]

Additionally, prioritizing sleep, maintaining a balanced diet, and avoiding excessive alcohol or substance use can improve overall mental health.

Prioritizing sleep helps stabilize moods and emotions while maintaining a balanced diet provides the body with essential vitamins and minerals to keep the mind functioning properly. Avoiding excessive alcohol and substance use ensures that the body is not introducing any chemicals or toxins into the system that could further damage mental health. All of these factors contribute to improved mental health, helping to reduce the symptoms of depression.

Talk to Your Doctor Before Making Changes to Your Treatment

If you continue to struggle with persistent depression symptoms or unwanted side effects, it may be time to talk to your doctor about making changes to your treatment. It’s important to discuss your side effects or concerns with your doctor, so they can help advise next steps. Sometimes, remission can by achieved by changing antidepressant medications or adding an augmenter. You may also ask them about all your mental health treatment options including drug-free alternatives, like TMS.

Key Takeaways:

  1. There is no one-size-fits-all approach when it comes to treating depression.
  2. Available treatments range from medication to various forms of therapy or a combination of multiple treatments, each with advantages and disadvantages.
  3. Ultimately, the choice of treatment should be based on each individual’s needs and in consultation with a healthcare professional.
  4.  Research is ongoing to refine and develop new treatment options, and it is important to remember that just because one medication may not have worked, it doesn’t mean another one won’t.

If you or a loved one is seeking relief from the burdensome symptoms of depression or another mental health condition, we invite you to take the first step towards a brighter future. Our team of highly trained professionals is dedicated to understanding your unique needs and crafting a comprehensive treatment plan tailored to your specific goals.

At Neuro Wellness Spa, we offer a range of innovative therapies and cutting-edge techniques that have shown remarkable success in achieving complete remission from symptoms like depression, anxiety, PTSD, and more. From transcranial magnetic stimulation (TMS) to medication management, our evidence-based treatments are designed to address the root causes of your condition and provide lasting relief. Contact us today to schedule an appointment with a psychiatrist and start this journey towards a healthier, happier you.


  1. Daly E, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):139–148. doi: 10.1001/jamapsychiatry.2017.3739.
  2. Gonda, X., Sharma, S. R., & Tarazi, F. I. (2019). Vortioxetine: a novel antidepressant for the treatment of major depressive disorder. Expert opinion on drug discovery, 14(1), 81–89.
  3. Hofmann, S. G., & Gómez, A. F. (2017). Mindfulness-Based Interventions for Anxiety and Depression. The Psychiatric clinics of North America, 40(4), 739–749.
  4. Iglesias A. H. (2020). Transcranial Magnetic Stimulation as Treatment in Multiple Neurologic Conditions. Current neurology and neuroscience reports, 20(1), 1.
  5. Karrouri, R., Hammani, Z., Benjelloun, R., & Otheman, Y. (2021). Major depressive disorder: Validated treatments and future challenges. World journal of clinical cases, 9(31), 9350–9367.
  6. Moraczewski J, Aedma KK. Tricyclic Antidepressants. [Updated 2022 Nov 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:
  7. Niciu, M. J., Henter, I. D., Luckenbaugh, D. A., Zarate, C. A., Jr, & Charney, D. S. (2014). Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds. Annual review of pharmacology and toxicology, 54, 119–139.
  8. Pigott H. E. (2015). The STAR*D Trial: It Is Time to Reexamine the Clinical Beliefs That Guide the Treatment of Major Depression. Canadian journal of psychiatry. Revue canadienne de psychiatrie, 60(1), 9–13.
  9. Schwasinger-Schmidt, T. E., & Macaluso, M. (2019). Other Antidepressants. Handbook of experimental pharmacology, 250, 325–355.
  10. Sheffler, Z. M., Patel, P., & Abdijadid, S. (2023). Antidepressants. In StatPearls. StatPearls Publishing.
  11. Sub Laban T, Saadabadi A. Monoamine Oxidase Inhibitors (MAOI) [Updated 2022 Jul 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from:

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