Medication to boost antidepressants

Is an Add-On Medication Right for Your Depression?

For most people with depression, prescription antidepressants help improve quality of life. But sometimes depression symptoms — like feelings of emptiness and hopelessness — just won’t go away. To help, your doctor might suggest an add-on medication, or augmentation therapy, to treat depression symptoms that persist.

“Sometimes when people have severe depression, they have a partial response to treatment,” says James Seymour, MD, a psychiatrist at Sierra Tucson, a behavioral treatment center in Tucson, Ariz. “They may need an add-on, or second, medication to improve or accelerate their response.”

The National Institutes of Mental Health funded a study on this very subject called STAR*D (Sequenced Treatment Alternatives to Relieve Depression). The seven-year study, which released initial results in 2006, looked at more than 4,000 people, ages 18 to 75, with depression. It found that those who did not improve with a single antidepressant medication had an increased chance of getting better with a new medication or through the addition of a second medication.

Is an Add-On Medication Right for You?

If you’ve noticed an improvement in your depression symptoms since starting an antidepressant but still feel like you could get better control, your doctor may recommend an add-on medication. Keep in mind, though, that you need to give your current medications a reasonable chance to work before looking at this option. It may take six or more weeks for an antidepressant to become fully effective. However, Dr. Seymour concedes that this can feel like a long time to wait if you aren’t seeing results. If after three weeks you see little or no improvement from your antidepressant, he suggests talking with your doctor about whether to wait the full six-week trial period before adjusting your dosage. For example, “if you’re taking 300 milligrams of an antidepressant and getting a partial response,” he says, “the next thing your doctor may do is to increase it to 450 milligrams.” If you increase the dosage, hit the maximum, and still see no improvement or have lingering symptoms, then you probably need to change to a different medication or use an add-on medication, Seymour says.

Your doctor might suggest adding a second antidepressant or a different kind of drug altogether. Some add-on depression medications are available as a combination pill, and some require that you take separate pills.

Add-On Medication Options for Depression

Among the different medications used as add-ons in depression treatment are:

  • Anti-anxiety medications or tranquilizers. Anti-anxiety medications (benzodiazepines) can boost the effectiveness of antidepressants on some depression symptoms. These medications slow down your central nervous system, making you feel more calm and relaxed. However, like all drugs, they can have side effects, and this class of medication does pose a risk of addiction for some.
  • Anticonvulsants. Typically given to prevent seizures in people who have epilepsy, anticonvulsants have been shown to have a calming effect on the brain and are sometimes used as an add-on medication for depression.
  • Antipsychotics. Used to treat delusions and hallucinations, these drugs may also have a benefit as an add-on medication for people with depression. Antipsychotics sometimes cause weight gain and carry an increased risk for insulin resistance (which can lead to diabetes) and cardiovascular disease, however, so this isn’t a first-line add-on medication option for people who already have these conditions.
  • Lithium. Generally well-tolerated as an add-on medication, lithium is usually used to treat bipolar disorder — a condition that involves moods that swing from high to low — and can help improve other mood disorders, including depression.
  • Thyroid hormone. This hormone is sometimes used as a depression treatment because many of the physical symptoms of major depression are similar to those of hypothyroidism (an underactive thyroid): fatigue, malaise, and cognitive impairment.

An add-on medication can help you combat depression if you’re not getting there on an antidepressant alone, but there are drawbacks. For one, taking more drugs can increase your chances of experiencing side effects. You and your doctor have to weigh the risks and benefits of add-on medications and decide what’s best for you. Unfortunately, Seymour says, there’s currently no scientific way to determine which add-on medication will be most effective from the start, so there may be some trial and error involved.

If you have relatives who also suffer from depression, look at the depression treatments that work best for them. How a person responds to a particular medication could be genetic, Seymour notes. Their success may give your doctor a starting point.

Chances are that with time and effort, you’ll find the best depression treatment for you. Only a small minority of people go through every available antidepressant alone and in combination without finding something that’s effective, Seymour says. “Roughly 60 percent of people get relief from their symptoms on the first try.” Of those who don’t, he says, about half get relief on the second try, and still others get relief on the third try. “So it’s only a small percentage who don’t respond to depression treatments alone or in combination,” he says.

“We are blessed to have a wide variety of antidepressants and add-on medications available to us today,” he adds. “Because we have many options, patients shouldn’t give up on finding a depression treatment that’s effective for them.”

Combination Therapies for Depression

If you have major depressive disorder (MDD), you’re likely already taking at least one antidepressant. Combination drug therapy is a type of treatment that many doctors and psychiatrists have been increasingly utilizing during the past decade.

The Role of Medications

Until recently, doctors prescribed an antidepressant medication from only a single class of drugs, one at one time. This is called monotherapy. If that drug failed, they might try another medicine within that class, or switch to another class of antidepressants entirely.

Research now suggests that taking antidepressants from multiple classes may be the best way to treat MDD. One study found that using a combination approach at the first sign of MDD may double the likelihood of remission.

Atypical Antidepressants

On its own, bupropion is very effective at treating MDD, but it may also be used in conjunction with other medications in difficult-to-treat depression. In fact, bupropion is one of the most commonly used combination therapy medications. It’s often used with selective serotonin reuptake inhibitors (SSRIs) and serotonin- norepinephrine reuptake inhibitors (SNRIs). It’s generally well tolerated in people who’ve experienced severe side effects from other antidepressant medication. It can also relieve some of the sexual side effects (decreased libido, anorgasmia) associated with popular SSRIs and SNRIs.

For people experiencing loss of appetite and insomnia, mirtazapine may be an option. Its most common side effects are weight gain and sedation. However, mirtazapine hasn’t been studied in depth as a combination medication.


Research suggests there may be some benefit in treating residual symptoms in people taking SSRIs with atypical antipsychotics, such as aripiprazole. The possible side effects associated with these medications, such as weight gain, muscle tremors, and metabolic disturbances, should be carefully considered as they may prolong or worsen some symptoms of depression.


Some doctors use L-Triiodothyronine (T3) in combination therapy with tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Research suggestions T3 is better at speeding up the body’s response to treatment than increasing the likelihood a person will enter remission.


D-amphetamine (Dexedrine) and methylphenidate (Ritalin) are stimulants used to treat depression. They can be used as monotherapy, but they may also be used in a combination therapy with antidepressant medications. They’re most helpful when the desired effect is a quick response. Patients who are debilitated, or those who have comorbid conditions (such as a stroke) or chronic medical illnesses, may be good candidates for this combination.

Combination Therapy as First-Line Treatment

Success rates of monotherapy treatment are relatively low, and therefore many researchers and doctors believe the first and best approach to treating MDD is combination treatments. Still, many doctors will begin treating with a single antidepressant medication.

Before making a decision about the medication, give it time to work. After a trial period (usually about 2 to 4 weeks), if you don’t show an adequate response, your doctor may wish to change medications or add an additional medication to see if the combination helps your treatment plan succeed.

So you go to your doctor or psychiatrist and you finally agree to take an antidepressant. Yet to your dismay you find that your depression symptoms are not fully going away. What now? In addition to talk therapy or other non-prescription remedies to treat depression your doctor may also recommend that you take an add-on or augmentation medication or supplement along with your antidepressant to increase its effectiveness. In a previous post I discussed how many of us are taking a “medication cocktail” which means we are using multiple medications for treating the same disorder. There are risks to taking any medication and this risk can be compounded when we take two or more medications to treat the same disorder or illness. Yet in some cases you and your doctor may decide that the possible benefits outweigh the risks so that you can effectively treat your depression.

In this on-going series we are going to talk about add-on or augmentation medications and supplements designed to enhance the effectiveness of your antidepressant. In this initial post we will discuss how to make that decision as to whether or not you need a second medication to treat your depression.

Safety First: Always research any prescription medications or supplements before you add them to your medication treatment plan. Discuss any potential drug interactions and side effects with your doctor or pharmacist.

Why would you need an add-on medication or supplement in addition to your antidepressant?

The Stanford Mood and Anxiety Disorders Laboratory reports that, in general, 2/3 of people who suffer from depression will respond to any given antidepressant. So that seems to leave a third who may be considered treatment resistant. The National Institute of Mental Health funded research they call the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study. This large scale study was created to judge the efficacy of various treatments for people who suffer from major depression who did not respond adequately to an initial treatment with an antidepressant.

Here are a couple of interesting things they found in doing this study:

  • For those people who don’t respond when one SSRI fails, approximately 1 in 4 people who switch to another antidepressant will get better regardless if the second medication is also an SSRI or if it is from another class of antidepressants such as an SNRI.

  • If a patient adds a new drug to their existing SSRI, 1 in 3 people will get better. They report that it makes little difference if the add-on drug is an antidepressant from a different class of drugs or if it is a medication designed to enhance or augment the SSRI.

This seems to offer hope for those folk who do not find relief from their initial attempt at taking an antidepressant.

Here are some general guidelines found in the literature as to steps to take when your first antidepressant doesn’t work:

1. Before you decide to take a second medication see if non-prescription treatments are an effective addition to your antidepressant.

Many patients respond favorably to a combination of medication and talk therapy. A 2004 Consumer Reports Survey of its readers found that patient respondents who reported that their therapy was “mostly talk” and lasted 13 sessions had better outcomes than those whose therapy was “mostly medication.” We have written extensively about other forms of non-medication including therapeutic massage, therapeutic laughter therapy, exercise, and changing your diet.

2. Give your antidepressant at least two months to fully take effect.

This is the recommendation given on the Stanford Mood and Anxiety Disorders Laboratory website. Antidepressants usually take a good 6-8 weeks to reach their full therapeutic effect. But sometimes they take a little more time. After taking an antidepressant for a full two months you can honestly say that you gave it a good chance. The main reason people usually quit before this time is up is due to adverse severe side effects. But in two months time many side effects will diminish. Another reason some will stop an antidepressant early on is a worsening of depression and a dramatic increase in suicidal thoughts.

If you are having any difficulties with your medication you need to speak with your doctor. Never quit a medication cold turkey as there is the potential for withdrawal symptoms and some can be severe.

3. Your doctor may opt to increase the dosage of your antidepressant.

The dosage of your medication is an extremely important key to whether or not your antidepressant will work for you. This is not an exact science and you may go through a period of months before the dosage of your antidepressant is at the peak therapeutic level for you. So many things can affect how your medication works. Your schedule of when you take your medication, foods you eat, and interactions with other supplements and medications can greatly affect the effectiveness of your antidepressant.

4. Your doctor may suggest switching you to a different antidepressant.

There are certainly many antidepressants to choose from nowadays. To read up on your choices please see our Antidepressant Drug Information guide.

5**. Your doctor may suggest an add-on or augmentation medication or supplement to enhance the effectiveness of the antidepressant you are already taking.**

It may be the case where your antidepressant is helping some but is not quite as effective as you would like. Instead of making a switch to a totally new medication, your doctor may opt to simply add on a second drug or supplement to augment or enhance your current antidepressant. There is a long list of add-on drugs which are prescribed for this purpose. In future posts we will explore some of these augmentation medications and how they work.

If you have depression that hasn’t responded to a single antidepressant, switching to another one or adding a second medication is your next step. New evidence is guiding what to do next if you aren’t much better after 6 – 12 weeks of treatment.

When your antidepressant isn’t working to improve or relieve your depressive symptoms, what’s your next step?

  • Don’t stop and switch. In adults with mild to moderate depression, augment (add to) your initial antidepressant with a second drug and/or psychotherapy rather than stopping and switching antidepressants. Adding a second med is where the benefit appears to be the strongest.
  • Don’t stop and try therapy alone. It is also recommended you add a second medication to your first medication instead of stopping meds altogether and trying therapy alone.
  • What’s the new info? In a recent study with 1500 patients with treatment-resistant depression, adding Abilify (aripiprazole) to their antidepressant led to more remission of symptoms than switching antidepressants. In this case, the original antidepressant was Wellbutrin (bupropion). It’s also important to know that most patients in this study were also receiving psychotherapy.
  • Which one should you add as a second medication? Ok, here’s where it gets fuzzy. For patients with treatment-resistant depression, there has been little comparative evidence to guide the choice for add-on therapy with a second medication. Basically, there isn’t yet good evidence to support one option over another.
  • Choices of second medications to add to your first antidepressant: Response (reduction of depression symptoms by 50 percent or more) or remission occurred more often with these 6 add-on medications, compared with placebo: Abilify (aripiprazole), lithium, Zyprexa (olanzapine), Seroquel (quetiapine), Risperdal (risperidone), or thyroid hormone (Cytomel, Synthroid, or levothyroxine). The benefits of each of these medications as a second choice were the same, so one has not been proven to be superior.
  • Downsides: Side effects are more common with two medications for depression instead of one: akathisia (crawling out of your skin feeling), sleepiness and weight gain were more commonly reported.
  • Take home message: Recent studies have shown that for patients who do not respond to a single antidepressant, add-on therapy may be modestly superior to switching antidepressants.

What has your experience been?

Dr O.

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  • SEROQUEL XR for Major Depressive Disorder

    Elderly patients with dementia-related psychosis (having lost touch with reality due to confusion and memory loss) treated with this type of medicine are at an increased risk of death, compared to placebo (sugar pill). SEROQUEL XR is not approved for treating these patients.

    Antidepressants have increased the risk of suicidal thoughts and actions in some children, teenagers, and young adults. Patients of all ages starting treatment should be watched closely for worsening of depression, suicidal thoughts or actions, unusual changes in behavior, agitation, and irritability. Patients, families, and caregivers should pay close attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. These symptoms should be reported immediately to the doctor. SEROQUEL XR is not approved for children under the age of 10 years.

      Do not take SEROQUEL XR if you are allergic to quetiapine fumarate or any of the ingredients in SEROQUEL XR.

      Stroke that can lead to death can happen in elderly people with dementia who take medicines like SEROQUEL XR.

      Stop SEROQUEL XR and call your doctor right away if you have some or all of the following symptoms: high fever; excessive sweating; stiff muscles; confusion; changes in pulse, heart rate, and blood pressure. These may be symptoms of a rare, but very serious and potentially fatal, side effect called neuroleptic malignant syndrome (NMS).

      High blood sugar and diabetes have been reported with SEROQUEL XR and medicines like it. If you have diabetes or risk factors such as obesity or a family history of diabetes, your doctor should check your blood sugar before you start taking SEROQUEL XR and also during therapy. If you develop symptoms of high blood sugar or diabetes, such as excessive thirst or hunger, increased urination, or weakness, contact your doctor. Complications from diabetes can be serious and even life threatening.

      Increases in triglycerides and in LDL (bad) cholesterol and decreases in HDL (good) cholesterol have been reported with SEROQUEL XR. Your doctor should check your cholesterol levels before you start SEROQUEL XR and during therapy.

      Weight gain has been reported with SEROQUEL XR. Your doctor should check your weight regularly.

      Tell your doctor about any movements you cannot control in your face, tongue, or other body parts, as they may be signs of a serious condition called tardive dyskinesia (TD). TD may not go away, even if you stop taking SEROQUEL XR. TD may also start after you stop taking SEROQUEL XR.

      Other risks include feeling dizzy or lightheaded upon standing, falls (which may cause serious injuries), trouble swallowing, or decreases in white blood cells (which can be fatal). Fever, flu-like symptoms, or any other infection could be a result of a very low white blood cell count. Tell your healthcare provider as soon as possible if you experience any of these.

      Before starting treatment, tell your doctor about all prescription and nonprescription medicines you are taking. Also tell your doctor if you have or have had low white blood cell count, seizures, abnormal thyroid tests, high prolactin levels, heart or liver problems, trouble emptying your bladder, enlarged prostate, constipation, increased pressure inside your eyes, or cataracts. An eye exam for cataracts is recommended at the beginning of treatment and every 6 months thereafter.

      Since drowsiness has been reported with SEROQUEL XR, you should not participate in activities such as driving or operating machinery until you know that you can do so safely. Avoid becoming overheated or dehydrated while taking SEROQUEL XR. Do not drink alcohol while taking SEROQUEL XR.

      Tell your doctor if you are pregnant or intend to become pregnant. Avoid breast-feeding while taking SEROQUEL XR.

      The most common side effects are drowsiness, dry mouth, constipation, dizziness, increased appetite, upset stomach, weight gain, fatigue, difficulty moving, disturbance in speech or language, and stuffy nose.

      Do not stop taking SEROQUEL XR without talking to your doctor. Stopping SEROQUEL XR suddenly may cause side effects.

    This is not a complete summary of safety information. Please discuss the full Prescribing Information with your health care provider.

    Approved Uses

    SEROQUEL XR is a once-daily tablet approved in adults for (1) add-on treatment to antidepressants for patients with major depressive disorder (MDD) who did not have an adequate response to antidepressant therapy; (2) acute depressive episodes in bipolar disorder; (3) acute manic or mixed episodes in bipolar disorder alone or with lithium or divalproex; (4) long-term treatment of bipolar disorder with lithium or divalproex; and (5) schizophrenia.

    Medications for Treatment-Resistant Depression

    Different antidepressants work in different ways to affect specific chemicals (neurotransmitters) that transmit information along brain circuits that regulate mood. If your current medicine isn’t helping – or isn’t helping enough – other drugs might. There are two basic approaches:

    • Switching medicines. There are a number of different classes of antidepressants, including SSRIs (such as citalopram , escitalopram , fluoxetine , fluvoxamine , paroxetine , and sertraline ) and SNRIs (such as desvenlafaxine , duloxetine , levomilnacipran , and or venlafaxine ). Newer antidepressant medicines that affect many different serotonin receptors in the brain include vilazodone (Viibryd) and vortioxetine (Trintellix, formerly called Brintellix). Older classes of antidepressants include tricyclics like doxepin (Adapin), amitriptyline (Elavil), imipramine (Tofranil), and nortriptyline (Pamelor, Aventyl); tetracyclics like amoxaoine (Asendin), maprotiline (Ludiomil,) mazindol (Mazanor); and mirtazapine (Remeron). Some antidepressants, such as bupropion (Wellbutrin) or mirtazapine (Remeron), are thought to affect the brain chemicals dopamine and norepinephrine through unique mechanisms, and are often combined with other antidepressants in order to take advantage of their combined effects. Another older class of antidepressants, called MAO inhibitors (such as isocarboxazid , phenelzine , selegiline , and tranylcypromine ) affect a special enzyme inside brain cells that can increase the functioning of several different neurotransmitters. Sometimes, switching from one class of antidepressant to another can make a difference.
      Another option is to switch from one drug to another in the same class. A person who wasn’t helped by one SSRI could still benefit from a different one. In addition, l-methylfolate (Deplin) has shown success in for treating treatment resistant depression. L-methylfolate is a prescriptionstrength form of the B-vitamin,folate, and helps regulate the neurotransmitters in the brain that control moods.
    • Adding a medicine. In other cases, your doctor might try adding a new medicine to the antidepressant you’re already using. This can be especially helpful if your current drug is partly helping, but not completely relieving your symptoms. This can be called adjunct therapy or augmenting treatment with another medicine.
      What medicines might he or she try? One option is to add a second antidepressant from a different class. This is called combination therapy. Another approach is called augmentation therapy: adding a medicine not typically used to treat depression, like lithium, an anticonvulsant, or an antipsychotic. Aripiprazole (Abilify), brexpiprazole (Rexulti) or quetiapine (Seroquel XR) are FDA approved as add-on therapies to an antidepressant for treatment-resistant depression. Olanzapine-Fluoxetine (Symbyax) is a combination drug that contains the active ingredients in fluoxetine (Prozac) and olanzapine (Zyprexa) together in one tablet and is approved for the acute treatment of treatment-resistant depression. One drawback to this approach is that the more medicines you take, the greater potential for side effects or drug interactions..
      People have different reactions to the drugs used for treatment-resistant depression. The medicine that works best for one person might have no benefit for you. And unfortunately, it’s hard for your doctor to know beforehand what drug or combination of drugs will work best. Arriving at the right treatment can take patience.

    You are now leaving the patient site


    REXULTI is a prescription medicine used to treat:

    • Major depressive disorder (MDD): REXULTI is used with antidepressant medicines, when your healthcare provider determines that an antidepressant alone is not enough to treat your depression.

    It is not known if REXULTI is safe and effective in people under 18 years of age.


    Increased risk of death in elderly people with dementia-related psychosis. Medicines like REXULTI can raise the risk of death in elderly who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). REXULTI is not approved for the treatment of patients with dementia-related psychosis.

    Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment. Depression and other serious mental illnesses are the most important causes of suicidal thoughts or actions. Some people may have a particularly high risk of having suicidal thoughts or actions. Patients on antidepressants and their families or caregivers should watch for new or worsening depression symptoms, especially sudden changes in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Report any changes in these symptoms immediately to the doctor. REXULTI is not approved for the treatment of people younger than 18 years of age.

    Do not take REXULTI if you are allergic to brexpiprazole or any of the ingredients in REXULTI. Allergic reactions have included rash, facial swelling, hives and itching, and anaphylaxis, which may include difficulty breathing, tightness in the chest, and swelling of the mouth, face, lips, or tongue.

    REXULTI may cause serious side effects, including:

    • Stroke in elderly people (cerebrovascular problems) that can lead to death.
    • Neuroleptic Malignant Syndrome (NMS): Tell your healthcare provider right away if you have some or all of the following symptoms: high fever, stiff muscles, confusion, sweating, changes in pulse, heart rate, and blood pressure. These may be symptoms of a rare and serious condition that can lead to death. Call your healthcare provider right away if you have any of these symptoms.
    • Uncontrolled body movements (tardive dyskinesia). REXULTI may cause movements that you cannot control in your face, tongue or other body parts. Tardive dyskinesia may not go away, even if you stop taking REXULTI. Tardive dyskinesia may also start after you stop taking REXULTI.

    • Problems with your metabolism such as:
      • high blood sugar (hyperglycemia): Increases in blood sugar can happen in some people who take REXULTI. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or having a family history of diabetes), your healthcare provider should check your blood sugar before you start taking REXULTI and during your treatment.

        Call your healthcare provider if you have any of these symptoms of high blood sugar while taking REXULTI:

        • feel very thirsty
        • feel very hungry
        • feel sick to your stomach
        • feel weak or tired
        • need to urinate more than usual
        • feel confused, or your breath smells fruity
      • increased fat levels (cholesterol and triglycerides) in your blood.
      • weight gain. You and your healthcare provider should check your weight regularly.
    • Unusual urges. Some people taking REXULTI have had unusual urges, such as gambling, binge eating or eating that you cannot control (compulsive), compulsive shopping and sexual urges.

      If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider.

    • Low white blood cell count
    • Decreased blood pressure (orthostatic hypotension). You may feel lightheaded or faint when you rise too quickly from a sitting or lying position.
    • Seizures (convulsions)
    • Problems controlling your body temperature so that you feel too warm. Avoid getting over-heated or dehydrated while taking REXULTI.
      • Do not over-exercise.
      • Stay out of the sun. Do not wear too
        much or heavy clothing.
      • In hot weather, stay inside in a cool
        place if possible.
      • Drink plenty of water.
    • Difficulty swallowing that can cause food or liquid to get into your lungs.

    Do not drive a car, operate machinery, or do other dangerous activities until you know how REXULTI affects you. REXULTI may make you feel drowsy.

    Before taking REXULTI, tell your healthcare provider if you:

    • have diabetes or high blood sugar or a family history of diabetes or high blood sugar. Your healthcare provider should check your blood sugar before you start REXULTI and during your treatment.
    • have high levels of cholesterol, triglycerides, LDL-cholesterol, or low levels of HDL cholesterol
    • have or had seizures (convulsions)
    • have or had low or high blood pressure
    • have or had heart problems or a stroke
    • have or had a low white blood cell count
    • are pregnant or plan to become pregnant. It is not known if REXULTI may harm your unborn baby. Using REXULTI in the last trimester of pregnancy may cause muscle movement problems, medicine withdrawal symptoms, or both of these in your newborn.
      • If you become pregnant while taking REXULTI, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit
    • are breastfeeding or plan to breastfeed. It is not known if REXULTI passes into your breast milk. You and your healthcare provider should decide if you will take REXULTI or breastfeed.

    Tell your healthcare provider about all the medicines you take or recently have taken, including prescription medicines, over-the-counter medicines, vitamins and herbal supplements.

    REXULTI and other medicines may affect each other causing possible serious side effects. REXULTI may affect the way other medicines work, and other medicines may affect how REXULTI works.

    Your healthcare provider can tell you if it is safe to take REXULTI with your other medicines. Do not start or stop any medicines while taking REXULTI without talking to your healthcare provider first.

    The most common side effects of REXULTI include weight gain and an inner sense of restlessness such as feeling like you need to move.

    Tell your healthcare provider if you experience abnormal muscle spasms or contractions, which may be a sign of a condition called dystonia.

    These are not all the possible side effects of REXULTI. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about your health or medicines, including side effects.

    You are encouraged to report side effects of REXULTI (brexpiprazole). Please contact Otsuka America Pharmaceutical, Inc. at 1‑800‑438‑9927 or FDA at 1‑800‑FDA‑1088 (



    On March 5, the Food and Drug Administration (FDA) approved the first truly new medication for major depression in decades. The drug is a nasal spray called esketamine, derived from ketamine—an anesthetic that has made waves for its surprising antidepressant effect.

    Because treatment with esketamine might be so helpful to patients with treatment-resistant depression (meaning standard treatments had not helped them), the FDA expedited the approval process to make it more quickly available. In one study, 70 percent of patients with treatment-resistant depression who were started on an oral antidepressant and intranasal esketamine improved, compared to just over half in the group that did not receive the medication (called the placebo group).

    “This is a game changer,” says John Krystal, MD, chief psychiatrist at Yale Medicine and one of the pioneers of ketamine research in the country. The drug works differently than those used previously, he notes, calling ketamine “the anti-medication” medication. “With most medications, like valium, the anti-anxiety effect you get only lasts when it is in your system. When the valium goes away, you can get rebound anxiety. When you take ketamine, it triggers reactions in your cortex that enable brain connections to regrow. It’s the reaction to ketamine, not the presence of ketamine in the body that constitutes its effects,” he says.

    And this is exactly what makes ketamine unique as an antidepressant, says Dr. Krystal.

    However, as the nasal spray becomes available via prescription, patients have questions: How does it work? Is it safe? And who should get it? Read on for answers.

    How do antidepressants work?

    Research into ketamine as an antidepressant began in the 1990s with Dr. Krystal and his colleagues Dennis Charney, MD, and Ronald Duman, PhD, at the Yale School of Medicine. At the time (as is still mostly true today) depression was considered a “black box” disease, meaning that little was known about its cause.

    One popular theory was the serotonin hypothesis, which asserted that people with depression had low levels of a neurotransmitter called serotonin. This hypothesis came about by accident—certain drugs given to treat other diseases like high blood pressure and tuberculosis seemed to drastically affect people’s moods. Those that lowered serotonin levels caused depression-like symptoms; others that raised serotonin levels created euphoric-like feelings in depressed patients. This discovery ushered in a new class of drugs meant to treat depression, known as selective serotonin reuptake inhibitors (SSRIs). The first one developed for the mass market was Prozac.

    But eventually it became clear that the serotonin hypothesis didn’t fully explain depression. Not only were SSRIs of limited help to more than one-third of people given them for depression, but growing research showed that the neurotransmitters these drugs target (like serotonin) account for less than 20 percent of the neurotransmitters in a person’s brain. The other 80 percent are neurotransmitters called GABA and glutamate.

    GABA and glutamate were known to play a role in seizure disorders and schizophrenia. Together, the two neurotransmitters form a complex push-and-pull response, sparking and stopping electrical activity in the brain. Researchers believe they may be responsible for regulating the majority of brain activity, including mood.

    What’s more, intense stress can alter glutamate signaling in the brain and have effects on the neurons that make them less adaptable and less able to communicate with other neurons.

    This means stress and depression themselves make it harder to deal with negative events, a cycle that can make matters even worse for people struggling with difficult life events.

    Ketamine—from anesthetic to depression “miracle drug”

    Interestingly, studies from Yale research labs showed that the drug ketamine, which was widely used as anesthesia during surgeries, triggers glutamate production, which, in a complex, cascading series of events, prompts the brain to form new neural connections. This makes the brain more adaptable and able to create new pathways, and gives patients the opportunity to develop more positive thoughts and behaviors. This was an effect that had not been seen before, even with traditional antidepressants.

    “I think the interesting and exciting part of this discovery is that it came largely out of basic neuroscience research, instead of by chance,” says Gerard Sanacora, MD, PhD, a psychiatrist at Yale Medicine who was also involved in many of the ketamine studies. “It wasn’t just, ‘let’s try this drug and see what happens.’ There was increasing evidence suggesting that there was some abnormality within the glutamatergic system in the brains of people suffering from depression, and this prompted the idea of using a drug that targets this system.”

    For the last two decades, researchers at Yale have led ketamine research by experimenting with using subanesthetic doses of ketamine delivered intravenously in controlled clinic settings for patients with severe depression who have not improved with standard antidepressant treatments. The results have been dramatic: In several studies, more than half of participants show a significant decrease in depression symptoms after just 24 hours. These are patients who felt no meaningful improvement on other antidepressant medications.

    Most important for people to know, however, is that ketamine needs to be part of a more comprehensive treatment plan for depression. “Patients will call me up and say they don’t want any other medication or psychotherapy, they just want ketamine, and I have to explain to them that it is very unlikely that a single dose, or even several doses of ketamine alone, will cure their depression,” says Dr. Sanacora. Instead, he explains, “I tell them it may provide rapid benefits that can be sustained with comprehensive treatment plans that could include ongoing treatments with ketamine. Additionally, it appears to help facilitate the creation new neural pathways that can help them develop resiliency and protect against the return of the depression.”

    This is why Dr. Sanacora believes that ketamine may be most effective when combined with cognitive behavioral therapy (CBT). CBT is a type of psychotherapy that helps patients learn more productive attitudes and behaviors. Ongoing research, including clinical trials, addressing this idea are currently underway here at Yale.

    A more patient-friendly version

    The FDA-approved drug esketamine is one version of the ketamine molecule, and makes up half of what is found in the commonly used anesthetic form of the drug. It works similarly, but its chemical makeup allows it to bind more tightly to the NMDA glutamate receptors, making it two to five times more potent. This means that patients need a lower dose of esketamine than they do ketamine. The nasal spray allows the drug to be taken more easily in an outpatient treatment setting (under the supervision of a doctor), making it more accessible for patients than the IV treatments currently required to deliver ketamine.

    But like any new drug, this one comes with its cautions. Side effects, including dizziness, a rise in blood pressure, and feelings of detachment or disconnection from reality may arise. In addition, the research is still relatively new. Studies have only followed patients for one year, which means doctors don’t yet know how it might affect patients over longer periods of time. Others worry that since ketamine is sometimes abused (as a club drug called Special K), there may be a downside to making it more readily available—it might increase the likelihood that it will end up in the wrong hands.

    Also, esketamine is only part of the treatment for a person with depression. To date, it has only been shown to be effective when taken in combination with an oral antidepressant. For these reasons, esketamine is not considered a first-line treatment option for depression. It’s only prescribed for people with moderate to severe major depressive disorder who haven’t been helped by at least two other depression medications.

    In the end, though, the FDA approval of esketamine gives doctors another valuable tool in their arsenal against depression—and offers new hope for patients no one had been able to help before.

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