Let's talk about Treatment-Resistant Depression!

You may have been suffering from depression for months, even years. You've seen a doctor and taken not one but two medications for the prescribed period of time, but your sadness, lack of interest in anything, or that unbearable sadness hasn't subsided at all. Then you may have what's called "Treatment-Resistant Depression" (TRD). Don't be alarmed when you hear that name, it doesn't mean "it can't be treated." However, it can take a while to find the right treatment for you. Let's talk about this in detail and very simply today.

What is this so-called treatment-resistant depression?

Simply put, 'treatment-resistant depression' is a subset of Major Depressive Disorder (MDD). It is diagnosed when you have depression and are taking at least two first-line antidepressants, at the recommended dose and for the recommended period of time (at least 6 to 8 weeks) , but your symptoms do not improve satisfactorily.

Doctors usually first prescribe medications from the `SSRI` (Selective Serotonin Reuptake Inhibitors) or `SNRI` (Serotonin and Norepinephrine Reuptake Inhibitors) group. This is because, compared to other antidepressants, these have fewer side effects, and the side effects are not as severe. Sometimes, even people who previously responded well to antidepressants can develop `TRD` later on. Despite the name, there are treatments for this too, but it can take some time to find the right one for you.

How common is this condition?

Did you know that approximately 30% of people diagnosed with major depressive disorder (MDD) and treated for it also have TRD? MDD is one of the most common mental health conditions in the world. It affects between 5% and 17% of people at some point in their lives. So, remember that you are not alone.

What are the symptoms of this?

People with `TRD` have the same symptoms as those with `MDD`. That is, things like constant sadness, melancholy, sleep disorders (either not falling asleep at all, or not being able to sleep), and changes in appetite (either not feeling like eating, or eating excessively).

However, these things are more common among people with `TRD`:

• Symptoms becoming more severe.
• Depression lasts for a long time.
• A condition called ``Anhedonia.'' It means that you are no longer able to derive any pleasure from things that used to bring you joy or pleasure. Imagine, you are listening to your favorite song or talking to a friend, but you feel no emotion.
• Increased frequency of experiencing depressive episodes during one's lifetime.
• Having excessive anxiety .
• Suicidal ideation and increased risk of attempting suicide .

Important: If you or someone you know is having thoughts of taking their own life, please call the Suicide and Crisis Lifeline on 988. Someone is available 24 hours a day to help you. You can also see a doctor or mental health counselor as soon as possible.

Why is this happening? What are the reasons?

In fact, researchers still don't know exactly why some people's depression doesn't respond to medication. Just as there is no single cause for depression, many factors, including genetic influences and changes in brain chemicals, contribute to this condition.

But, they think, chronic stress can have a big impact on this. How do you know? We have an important system in our bodies called the `Hypothalamic-Pituitary-Adrenal (HPA) axis. This is what helps us adapt to stress. So, ongoing stress can change the functioning of this `HPA` axis. When that happens, depression becomes more severe and harder to treat.

Who is most at risk?

Research has shown that, compared to people with MDD who respond to medication, people with TRD are more likely to have the following physical conditions:

• Autoimmune diseases (that is, diseases in which the body's immune system attacks itself).
• Thyroid disease.
• Heart disease.
• Cerebrovascular disease (that is, diseases that occur in the vessels that supply blood to the brain).

Not everyone with these diseases will develop TRD, but these may be risk factors.

How do doctors diagnose this accurately?

The diagnosis of `TRD` is not very clearly defined. However, most doctors diagnose this condition when you have not seen any improvement in your depressive symptoms after taking at least two of the antidepressants that you are currently using. Doctors often consider the following as first-line antidepressants:

• `SSRIs`
• `SNRIs`
• Bupropion
• Mirtazapine

Generally, you need to use a medicine for at least six to eight weeks to see if it works or not.

If you're taking two medications and still not feeling any improvement, your doctor may refer you to a psychiatrist . There, he or she will take a thorough medical and mental health history. This may include:

• Ask about all the medications you are currently taking (prescribed by your doctor, over-the-counter, herbal remedies, even narcotics) . Some medications can interfere with the effectiveness of antidepressants or even make depression worse.
• They will discuss whether you are taking antidepressants and other medications correctly and as prescribed .
• They will check if you have received psychotherapy or talk therapy and if it has helped with your depression.
• Some physical conditions, such as thyroid disease and chronic pain, can cause or exacerbate depression, so they are checked for.
• They check for problems like drug use .
• Consider whether your symptoms are more likely to be diagnosed with another mental health condition (e.g., bipolar disorder or personality disorder) .

After discussing all of this and performing the necessary tests, your doctor will determine whether you have `TRD` or not. Then, he or she will help you find the best treatment option for you.

So what are the treatments for this?

There are several ways to control `TRD.` It may take some time to get the desired results, but don't give up hope.

First, your psychiatrist may try these things:

• Give the antidepressant you are currently taking a little more time to work.
• Increase the dosage of a first-line antidepressant you are currently taking.
• Add an antidepressant from another class. Then you're taking two medications at once.
• Encourage yourself to meet with a psychologist and get psychotherapy . It can take some time to find a therapist who "gets you." Also, there are different types of psychotherapy.

What do you do next when normal treatments don't work?

If these basic methods don't work, your psychiatrist will often recommend a different type of medication, a combination of medications, or a different treatment method.

Currently, the US Food and Drug Administration (FDA) has approved five drugs for TRD:

• Aripiprazole (Abilify®) and Brexpiprazole (Rexulti®): These are third-generation antipsychotic medications. They can reduce symptoms of depression by affecting the levels of serotonin and norepinephrine in your brain.
• Quetiapine (Seroquel®) and Olanzapine (Zyprexa®): These are second-generation antipsychotics. Quetiapine is approved as an adjunctive treatment for TRD with antidepressants. Olanzapine is approved when given in combination with Fluoxetine (Prozac®). They help reduce symptoms of depression by affecting dopamine levels in the brain. These medications can also cause drowsiness.
• Esketamine nasal spray (Spravato®): This is made from a substance called ketamine. The FDA approved it in 2019 as an add-on treatment for adults with TRD, along with an oral antidepressant. Esketamine can start to reduce symptoms of depression within about two hours of taking it. However, because it can cause excessive sleepiness (sedation), dissociation (loss of awareness of where you are or what is happening), and because it can be abused, this medication is only given under the supervision of a doctor in a clinic. Doctors will monitor you for two hours after taking the medication.

What other treatments are FDA approved?

The FDA has also approved these treatments for TRD:

• Electroconvulsive therapy (ECT): This is a medical procedure. In this, very mild electrical impulses are sent through your brain, causing a small seizure. This stimulates nerve cells and can cause changes in the brain that improve your mood.
• Repetitive transcranial magnetic stimulation (rTMS): This is a noninvasive treatment. In this treatment, a magnetic coil is used to influence the natural electrical activity of your brain. This can cause changes in specific areas of the brain that affect your mood.

Are there other treatment options?

There are several other treatment options for TRD, but these may not be widely available or may still be in the research stage:

• Deep brain stimulation (DBS): This is also a medical procedure. Here, a gentle electrical current is delivered to a specific part of your brain. This electricity stimulates brain cells in that area, which can provide relief from several conditions, including TRD.
• Lithium (Eskalith®): Research has shown that taking lithium with an antidepressant (e.g., citalopram) can improve TRD.
• `MAOI` (Monoamine oxidase inhibitors): These were the first antidepressants to be discovered. However, because of the many restrictions on food intake, side effects, and safety concerns, doctors only prescribe them when all other antidepressants have failed.
• Pramipexole (Mirapex®): This is an FDA-approved medication for Parkinson's disease. Studies have shown that it can reduce depressive symptoms in Parkinson's disease. It may also help people with TRD.
• Vagus nerve stimulation (VNS): Here, a device is implanted that sends regular, gentle electrical pulses to the brainstem through the vagus nerve in your neck. This can change the levels of certain neurotransmitters in the brain that control your mood.

Researchers are also studying psilocybin, a compound isolated from hallucinogenic mushrooms, as a treatment for TRD.

Are there any side effects to these treatments?

In general, medications and treatments for `TRD` can have more side effects than first-line antidepressants. Also, those side effects can vary greatly. Your doctor will talk to you about the possible side effects or complications of each treatment option. Don't hesitate to ask questions.

Can this situation be prevented from occurring?

Because scientists don't know exactly what causes TRD, it's usually difficult to prevent it. However, since chronic stress can contribute to it, you can do these things to manage your stress:

• Exercise regularly. Even a short walk can improve your mood.
• Get good sleep. This is essential for overall health.
• Try things like meditation, yoga, breathing exercises, and muscle relaxation exercises .
• Set goals for your day, week, and month. When you focus on the little things, you'll feel like you have control over the moment and the long-term.
• Practice mindfulness and gratitude . Think about the good things in your day or life.
• Get into the habit of saying "no" to extra responsibilities when you're busy or stressed.
• Maintain relationships with people who keep you calm, support you emotionally, and help you with practical things.
• Consider talking to a therapist or your doctor about stress.

If you have treatment-resistant depression, what can you do at home?

In addition to seeking professional, medical help for TRD, there are several things you can do at home that may help reduce your symptoms:

• Exercising regularly.
• Getting good quality sleep (neither oversleeping nor undersleeping).
• Eating a healthy diet.
• Avoid alcohol and nonmedical drugs. Alcohol is a depressant.
• Spending time with those you love and care about.

When should you see a doctor?

Until you find an effective treatment plan for TRD that works for you, you should see your doctor regularly to see how it's working.

Apart from that, talk to your doctor in these cases:

• If you experience bothersome side effects.
• If your symptoms do not improve, or if they get worse.
• If you are thinking of stopping your medication (never stop taking medication without medical advice).

The most important thing you have to say

If you have `TRD`, first remember that you are not alone . About 30% of people with major depression have this condition. There are several treatment options for `TRD`, but it can take some time to find the one that works best for you. Your doctor and/or psychiatrist will support you on that journey. Never give up hope. With the right support and treatment, you can manage this condition and live a better life.

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