Let's Talk About Depression Medication
Antidepressants and other depression-fighting meds are thought to help restore the balance of chemicals called neurotransmitters in the brain. Understanding your options and figuring out which drugs work best for you can be a game-changer for easing depression.by Meirav Devash Wellness Writer
When you’re clinically depressed, your brain tells you all kinds of things about yourself, including that you can never get better. You might believe that your depression is too stubborn, that the medications that lift other people out of depression won’t work for you, and that even if you try your hardest, nothing will ever change. But there is proven hope! Antidepressants and psychotherapy are the first-line treatments for depression. Makes sense, since research comparing antidepressants to psychotherapy says they’re about equally effective. Pairing them together is even better. It can take several tries before you find the antidepressant or combination of medications that work best for you, but you can get there.
Our Pro Panel
We asked some of the nation's top depression experts to bring you the most up-to-date information possible.
James B. Potash, M.D., M.P.H.
Henry Phipps Professor of Psychiatry and Behavioral Sciences, Department Director and Psychiatrist-in-Chief
Johns Hopkins School of Medicine
Charles B. Nemeroff, M.D., Ph.D.
Chief Medical Officer of the Anxiety and Depression Association of America, Professor and Chair of Psychiatry at Mulva Clinic for the Neurosciences
Dell Medical School, The University of Texas
Seema Desai, M.D.
Clinical Assistant Professor, Psychiatrist
Department of Child and Adolescent Psychiatry, NYU School of Medicine; NYU School of Medicine WTC Health Program Clinical Center of Excellence
New York, NY
Nope! You know how when you take antibiotics, you feel better after a few days but your doctor makes you take the whole antibiotic regimen so your infection can be fully wiped out? This is kind of the same concept. After an episode of depression, there is a 50% risk that you’ll have another one (after two or three episodes, your risk is much higher). That’s why you should never discontinue your medication without talking to your doctor, and why most experts suggest staying on antidepressants for six to nine months after you feel that you’ve fully recovered—to prevent a relapse. If your depression is chronic, your psychiatrist might suggest you stay on a maintenance dose indefinitely.
Yes, but only to a certain degree. It only takes a quick mouth swab to take a pharmacogenomic test that will analyze your genes and determine which medications are best metabolized (broken down) by your body. If you metabolize a drug too quickly, it might leave your bloodstream before it fully takes effect, so you’d need a higher dose. If you metabolize a medicine too slowly, it can hang around for too long and increase the chance of side effects, so you might need a lower dose. This test can determine which medications are just right for your body’s metabolism. But just because your body can metabolize a drug properly doesn’t mean it is the most effective choice for your depression, which is why some clinicians currently question the relevance of these types of tests. Plus, genetic testing is often prohibitively expensive and, in many cases, not covered by insurance. In 2018, the FDA came out against the use of many genetic tests to predict patient response to specific drugs, saying that “for most medications, the relationship between DNA variations and the medication's effects has not been established.”
It’s known as "Discontinuation Syndrome", and 20% of patients who abruptly reduce their SSRI medication dose or stop completely experience symptoms, which typically show up two to four days after quitting antidepressants cold turkey. Those symptoms include nausea, diarrhea, dizziness, numbness, flu-like symptoms, sadness, emotional sensitivity, and sleep issues. Always talk to your doctor before going off your meds or moving to a lower dose; your doc can give guidance on how to wean off so you don’t have negative side effects.
As far as we’re concerned, none of them. Before we even get into this conversation, let’s address the fact that the supplement industry is not FDA-regulated. As a consequence, bottles of herbal medicines, supplements, and vitamins don’t always contain what the label claims they do. Even if they did, many herbal remedies interfere with prescription medicines and can cause serious, sometimes fatal, interactions. You can find loads of anecdotal evidence for the depression-fighting properties of many popular supplements like St. John’s wort, fish oil, folic acid, SAMe, and 5-HTP, but more scientific research is needed to back up those claims. They are not a replacement for treatment from a medical professional. If you’re thinking of taking any OTC treatments, make sure to run it by a doctor for possible drug interactions and buy them from a reputable supplier. A good way to find out which supplements pass muster is checking with an independent lab, like ConsumerLab.com or LabDoor, that test them and publishes their rankings.
What You Need to Know First
You may be eager to start meds—we get it, you want your symptoms tamped the hell down. And on the right treatment, that will happen. But prepare yourself: There are a slew of pill options, and doctors can't predict who's going to respond best to which ones.
Those genetic tests that claim to take away the guesswork from medication choices? They can tell you which drugs you won’t and will metabolize well, but there’s no telling which of the latter will work better for you. That means trial and error is simply part of the treatment experience. Your doctor may prescribe one (or more) of several types of antidepressants and/or atypical antipsychotic pills to customize an effective treatment.
Where do they even start with meds? Psychiatrists know a medication won’t work if a patient stops taking it early because of side effects or feeling like it isn’t “kicking in.” So they often choose your first-line treatment based on side effects that'll be a deal breaker for you. For example, if you have an eating disorder or are concerned about weight gain, they'll go for a drug that doesn't affect weight. If you're already falling asleep at 2 p.m., they won't pick meds associated with fatigue.
If you don’t respond to a particular medication or a class of drugs, your doctor will try another. This process can be frustrating for doctors and patients. When patients are feeling desperate, the last thing they want to hear from their doc is that it may take weeks or even months to figure out a solution.
Psychiatrists' message to patients? Bear with us. We're going to find the right combination for you, it just might take a while. In fact, the largest, longest-standing study of depression treatments to date showed that when patients tried four antidepressants over the course of five years, about 70% of them no longer had depressive symptoms.
What Do Antidepressants Do?
Depression is a complicated disorder that scientists have simplified for the layperson as a “chemical imbalance” involving monoamine neurotransmitters—chemical messengers in the brain that help regulate people’s mood, digestion, sleep, and other body functions.
Antidepressant medications increase the availability of neurotransmitters like serotonin and norepinephrine seen in people with clinical depression. There are several types of antidepressants and other medications that may be prescribed for depression.
SSRIs (Selective Serotonin Reuptake Inhibitors)
The most commonly prescribed antidepressants, SSRIs, boost levels of serotonin in the brain, which is thought to contribute to functions including regulating body temperature, sleep, mood, appetite, and pain.
SSRIs are “selective” because they affect serotonin, not other neurotransmitters like norepinephrine or dopamine.
They work by blocking reabsorption (i.e. reuptake) of serotonin into neurons, leaving more serotonin available to improve communication between neurons.
Common SSRIs include:
Paxil, Pexeva (paroxetine)
Possible side effects of SSRIs as a drug class (meaning, not every drug will have every side effect) include:
Nausea, vomiting, diarrhea
SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors)
SNRIs increase levels of neurotransmitters serotonin and norepinephrine in the brain by blocking their reabsorption (i.e. reuptake).
These meds are newer than SSRIs and some research shows they work slightly (5%-10%) better.
We talked about what serotonin does before; the other neurotransmitter SNRIs affect is norepinephrine, which is thought to control attentiveness, emotions, sleep, and learning. Norepinephrine is also released into the blood as a hormone, causing vessels to contract and your heart rate to increase, as in fight-or-flight situations.
Common SNRIs include:
Effexor XR (venlafaxine)
Possible side effects of these SNRIs include:
Loss of appetite
MAOIs (Monoamine Oxidase Inhibitors)
These were the first antidepressant category, born way back in the 1950s when doctors found that a derivative of a tuberculosis-fighting drug called Marsilid (iproniazid) helped relieve the symptoms of depression. It worked by stopping an enzyme called monoamine oxidase from breaking down neurotransmitters like serotonin, norepinephrine, and dopamine in the brain.
These drugs aren’t used as often today because they’re associated with unpleasant side effects (the usual sexual problems and dizziness) but also have potentially dangerous interactions with other antidepressants, seizure medications like carbamaze, and even decongestants like Sudafed (pseudoephedrine, phenylephrine), which can trigger a hypertensive episode.
MAOIs can also put a major cramp in your diet.
For example, your blood pressure can spike dangerously high if you take MAOIs and eat tyramine-rich foods like aged cheese, cured meats, beer, and soy sauce. Still, this category of drugs remains an effective option for people whose depression hasn’t responded to SSRIs and SNRIs.
Common MAOIs include:
Possible side effects of MAOIs are:
Nausea, diarrhea, constipation
Dizziness or lightheadedness
Involuntary muscle jerks
Low blood pressure
Difficulty starting a urine flow
A new MAOI called selegiline—sold under the brand names Emsam, Eldepryl, and Zelapar—works by selectively blocking monoamine oxidase B (MAO-B) from metabolizing dopamine. Thought to control posture, movement, and mood, dopamine is also involved with positive reinforcement and dependency.
One notable difference from other MAOIs is Emsam’s unique delivery system—it’s the first transdermal patch for depression (all the others are pills). Since it skips the GI tract, there are no dietary restrictions at the effective dose of 6 mg every 24 hours, which means you might not need to give up on beer and cheese just yet.
TCAs (Tricyclic Antidepressants)
Another old-school medication category from the 1950s. TCAs work much like reuptake inhibitors by blocking the reabsorption of serotonin and norepinephrine. They also affect other brain chemicals.
TCAs are not used as often these days, since they have interactions with numerous drugs like heartburn drug Tagamet (cimetidine) and stimulant Ritalin (methylphenidate) which increases the its toxicity.
TCAs can cause unpleasant side effects like tremors, hypotension, sexual difficulties—par for the course—but they’re also more toxic. While it’s possible to overdose on any antidepressant, TCAs cause the highest number of fatal overdoses.
Still, people with bipolar disorder, PDD, MDD, OCD, and PTSD who haven’t responded well to SSRIs and SNRIs can see good results with TCAs.
Common TCAs are:
Possible side effects include:
This type of med works differently than the ones listed above. Typical antidepressants boost availability of neurotransmitters serotonin or norepinephrine (or both) in the synapse, the site where electric impulses between two nerve cells happen.
These drugs use a different mechanism. Two common atypical antidepressants:
Bupropion is an NDRI (norepinephrine-dopamine reuptake inhibitor), which stops the reuptake of dopamine and norepinephrine. It also blocks receptors where nicotine binds, so many doctors also prescribe it when patients want to quit smoking. Bupropion isn’t known for causing sexual side effects or weight gain, which are both big reasons people stop other antidepressant meds, so this is a good option if side effects from other meds are bad.
Symbyax (olanzapine and fluoxetine) is a combination of SSRI fluoxetine and antipsychotic olanzapine, generally prescribed for bipolar depression or treatment-resistant depression.
Additional examples of atypical antidepressants:
Wellbutrin, Chantix, Zyban, Aplenzin, Budeprion, Forfivo (bupropion)
Possible side effects include:
These second-generation antipsychotics are “atypical” in that they affect dopamine and other neurotransmitters without the physical side effects, such as tics and tremors, that first-generation antipsychotics can cause (though “regular” antipsychotics still exist and docs still prescribe them for some patients).
They’re primarily used for treating psychosis, but research shows they can help people with depression and anxiety disorders. In this case, doctors prescribe them as "augmenters" (add-ons) to SSRIs and SNRIs when antidepressants alone only provide partial relief of symptoms.
Common atypical antipsychotics include:
Possible side effects are:
High blood pressure
Impulse control problems
Rare but serious skin reaction
Other Drug Treatment Approaches
Researchers haven’t just been sitting on their butts. When it comes to better living through chemistry, there have been a few cool innovations lately.
The Steroid: Zulresso (Brexanolone)
Zulresso, a version of the body’s own neurosteroid called allopregnanolone, became the first FDA-approved treatment for Postpartum Depression (PPD) in March 2019.
This drug works through a totally different system than serotonin or norepinephrine—instead, it binds to gamma-aminobutyric acid (GABA) receptors, which play a part in reducing stress and anxiety.
The good news? It starts working almost immediately and results last up to 30 days after infusion, which is a big deal when you’re in crisis and responsible for a newborn.
More details on Zulresso:
It’s a pricy endeavor, though. Brexanolone costs $34,000 on average (!!!) plus the cost of a days-long hospital stay. Depending on your provider and coverage plan, your insurance may cover at least part of treatment.
It's only approved for PPD, which means everyone who isn’t a new mother with acute depression isn’t a candidate for this treatment. That said, Sage Pharmaceuticals, Zulresso’s parent company, hopes that the drug will be approved for MDD soon.
It has to be delivered as an IV infusion over 60 hours, which means that you need to be hospitalized for about three days. Sage Pharmaceuticals is working on a brexanolone-esque pill to treat patients outside of a hospital setting. (Unfortunately, the drug didn’t do too well against placebo in their latest clinical trial, so it’s back to the lab for the moment.)
Currently, you can only get it through a program at certified healthcare facilities, under 24-hour supervision in case of possible side effects like oxygen deficiency and excessive sedation (a rare side effect is suddenly losing consciousness).
The Former Party Drug: Spravato (Esketamine)
Ketamine (a.k.a. on the party scene as Special K) in its original form is an anesthetic used for surgical procedures since the 1970s, but it wasn’t until the 2000s that clinics across the country started offering off-label IV infusions of ketamine to treat pain and depression.
The FDA recently approved Spravato nasal spray, a potent, fast-acting form of ketamine, for use along with an oral antidepressant for treatment-resistant depression. Scientists believe it works as an NMDA receptor antagonist, which inhibits the action of the N-Methyl-D-aspartate receptor, to activate a neurotransmitter called glutamate.
Esketamine is the first new type of drug approved by the FDA for severe depression in decades, and the only fast-acting FDA-approved antidepressant available for treatment-resistant depression. (Unlike most antidepressants, which take weeks to work, patients report feeling effects of esketamine within days or even hours. Speed is a particularly big deal when someone has severe depression and is exhibiting suicidal thoughts or behavior.)
The drawbacks to this spray are it needs to be self-administered in a clinical setting (yes, you have to go somewhere to administer it yourself) under supervision of a mental health professional. Doctors aren’t trying to let you disappear into a K-hole.
It’s classified as a Schedule III drug by the FDA, which means it can be addictive. And it’s expensive, at up to $5,000 per month, though your insurance may reimburse you.
Researchers are currently studying other psychedelics, such as psilocybin (the active ingredient in magic mushrooms) and LSD, that may have clinically significant antidepressant effects.
How Long Does It Take Depression Medications to Work?
Some improvement in symptoms can often be felt within 72 hours, but it can take six weeks or longer to fully feel the effects of antidepressant pills. (Exceptions to this rule include faster-acting therapies for severe or treatment-resistant depression like ketamine therapy, Spravato esketamine nasal spray, and the neurosteroid Zulresso.)
If your depression symptoms haven’t improved after a few weeks, your psychiatrist may increase your dose, switch you to another medication, or augment your medication with an atypical antipsychotic.
This is the dreaded trial-and-error we were talking about, but it’s an essential component to your treatment.
Also, very important to know for patients under age 25: In some cases, they may experience suicidal thoughts in the first few weeks on a new antidepressant or new dose. This is why doctors will often start them off on a lower dose to help prevent this effect.
How Long Will I Have to Take Antidepressants?
Only until you’re completely recovered from your depressive episode. That’s not when you think it is, by the way—experts agree it’s safest to stay on antidepressants for six to nine months after you officially feel better in order to stave off a relapse.
The risk, of course, is that once you go off your meds, you’ll start feeling depressed again. So be prepared to change course if you need to! If you’ve had previous depressive episodes or your depression is chronic, your psychiatrist might suggest you stay on a maintenance dose indefinitely.
What Happens When I Go off Antidepressants?
Some people say they’re in “withdrawal” when they stop taking their depression meds—but “withdrawal” would suggest that you are addicted to the drug, which doesn’t apply here. Symptoms of going off antidepressant meds too quickly or titrating to a lower dosage too dramatically is actually called discontinuation syndrome.
Going off your meds doesn’t necessarily mean you’ll be affected by discontinuation syndrome, especially if you do so under the supervision of a doctor. Research shows that only 20% of patients who abruptly reduce their medication dose or quit altogether experience issues. Symptoms generally start two to four days after quitting antidepressants cold turkey, especially if you’ve been taking them continuously for at least a month.
If you’re considering lowering your dosage or coming off SSRIs entirely, it’s important to work with your doctor to develop a plan to wean off slowly. This will allow your body to adjust with as little discomfort as possible. Keep your doctor in the loop about any re-emerging or new symptoms that might require treatment. They might ease you along with a different antidepressant or short-term anti-anxiety pills as you transition.
The symptoms of antidepressant discontinuation syndrome include:
Digestive issues (nausea, cramps, diarrhea)
“Brain zaps” (they feel like an electric shock to your head)
Sleep issues (trouble sleeping, nightmares)
Feelings such as being on the verge of crying such as “heavy heart”
Yes, some of the potential side effects of these meds are scary. And yes, finding the right antidepressant(s) can be a difficult road. But know this: By working closely with your psychiatrist, you can find a medication regimen that works for you and helps get you back to feeling good again.
Antidepressants vs. Psychotherapy: JAMA Psychiatry. (2014). “Effect of Cognitive Therapy With Antidepressant Medications vs Antidepressants Alone on the Rate of Recovery in Major Depressive Disorder: A Randomized Clinical Trial.” jamanetwork.com/journals/jamapsychiatry/fullarticle/1897300
STARD: Cleveland Clinic Journal of Medicine. (2008). “The STARD study: Treating depression in the real world.” researchgate.net/publication/5614758_The_STARD_study_Treating_depression_in_the_real_world
Neurotransmitters: McGill University. (n.d.) “The Brain From Top to Bottom.” thebrain.mcgill.ca/flash/i/i_01/i_01_m/i_01_m_ana/i_01_m_ana.html
SSRIs for Depression: Mayo Clinic. (2019). “Selective Serotonin Reuptake Inhibitors (SSRIs).” mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825
SNRIs for Depression: Mayo Clinic. (2019). “Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs). mayoclinic.org/diseases-conditions/depression/in-depth/antidepressants/art-20044970
MAOIs for Depression: Neuropsychiatric Disease and Treatment. (2007). “Transdermal selegiline for the treatment of major depressive disorder.” ncbi.nlm.nih.gov/pmc/articles/PMC2656289/
TCAs for Depression: Mayo Clinic. (2019). “Tricyclic antidepressants and tetracyclic antidepressants.” mayoclinic.org/diseases-conditions/depression/in-depth/antidepressants/art-20046983
Atypical Antidepressants for Depression: Mayo Clinic. (2019). “Atypical Antidepressants.” mayoclinic.org/diseases-conditions/depression/in-depth/atypical-antidepressants/art-20048208
Atypical Antipsychotics for Depression (1): Pharmacotherapy. (2013). “Augmentation with Atypical Antipsychotics for Depression: A Review of Evidence‐Based Support from the Medical Literature.” accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/phar.1204
Atypical Antipsychotics for Depression (2): U.S. Food and Drug Administration. (2016). “FDA Drug Safety Communication: FDA warns about rare but serious skin reactions with mental health drug olanzapine (Zyprexa, Zyprexa Zydis, Zyprexa Relprevv, and Symbyax).” fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-rare-serious-skin-reactions-mental-health-drug
Atypical Antipsychotics for Depression (3): U.S. Food and Drug Administration. (2016). “FDA Drug Safety Communication: FDA warns about new impulse-control problems associated with mental health drug aripiprazole (Abilify, Abilify Maintena, Aristada).” fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-new-impulse-control-problems-associated-mental-health
Zulresso for Depression (1): U.S. Food and Drug Administration. (2019). “FDA approves first treatment for post-partum depression.” fda.gov/news-events/press-announcements/fda-approves-first-treatment-post-partum-depression
Zulresso for Depression (2): MGH Center for Women’s Mental Health. (2019). “Moving Forward with Brexanolone (Zulresso): Pilot Program at the Cleveland Clinic.” womensmentalhealth.org/posts/moving_forward_with_brexanolone/
Zulresso for Depression (3): The Lancet. (2018). “Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials.” thelancet.com/journals/lancet/article/PIIS0140-6736(18)31551-4/fulltext
Zulresso for Depression (4): Business Wire. (2019). “Sage Therapeutics Reports Topline Results from Pivotal Phase 3 MOUNTAIN Study of SAGE-217 in Major Depressive Disorder.” businesswire.com/news/home/20191205005375/en/Sage-Therapeutics-Reports-Topline-Results-Pivotal-Phase
Ketamine and Esketamine for Depression (1): World Health Organization. (2015). “WHO Recommends against International Control of Ketamine.” who.int/medicines/access/controlled-substances/recommends_against_ick/en/
Ketamine and Esketamine for Depression (2): Mayo Clinic. (2019). “Mayo Clinic Q and A: New treatment for hard-to-treat depression.” newsnetwork.mayoclinic.org/discussion/mayo-clinic-q-and-a-new-treatment-for-hard-to-treat-depression/
Psychedelics for Depression: New York Times. (2019). “Johns Hopkins Opens New Center for Psychedelic Research.” nytimes.com/2019/09/04/science/psychedelic-drugs-hopkins-depression.html
Treatment Length: The Primary Care Companion to The Journal of Clinical Psychiatry. (2001). “Steps Following Attainment of Remission: Discontinuation of Antidepressant Therapy.” ncbi.nlm.nih.gov/pmc/articles/PMC181183/