How Antidepressant Withdrawal Makes Symptoms More Severe

Each year, more than 16.1 million adults in the United States are affected by major depressive disorder, making it the leading cause of disability in adults aged from 15 years old to 44.3 years old, according to the Anxiety and Depression Association of America. More than one-third of adults with depression go untreated, while half receive either medication on its own or help from a health professional in combination with medication. Treatment often includes an antidepressant.

Antidepressants are used not only to treat patients with depression but also those suffering from other conditions including obsessive-compulsive, generalized anxiety, and eating disorders.

However, the use of antidepressants, like other medications, comes with potential side effects. A recent study observed that some of these side effects may appear upon stopping the medication.

Types of Depression

There are many different types of antidepressants, but before we get into those, it’s important to be aware that depression may take many forms as well.

Major depressive disorder is the most commonly diagnosed form of depression. Its symptoms include feeling sad, empty, guilt, worthless, or hopeless; exhibiting bursts of anger or irritability; fatigue or lack of energy; significant changes in weight and appetite (either reduced appetite and weight loss or increased food cravings and weight gain); difficulty concentrating, thinking, and making decisions; and anxiety. Most people experience some of these symptoms at some point in their lives, usually with an explanation. For people with major depressive disorder, the symptoms last most of the day and occur almost every day, not only during periods of sadness. Often, these symptoms interfere with activities of daily living, such as work, school, and social life.

Persistent depressive disorder, or dysthymia, refers to long-term depression. This chronic condition can continue for years and significantly affect one’s quality of life. Unlike major depressive disorder, symptoms may not be as severe, although they may range in severity over the years and come and go at different times. Patients with persistent depressive disorder may be described by others as “gloomy.” Some symptoms of persistent depressive disorder are similar to those of major depressive disorder. Signs may include loss of interest in daily activities, avoiding social activities, tiredness and lacking energy, feeling sad/down or empty, difficulty concentrating and making decisions, and decreased activity and productivity.

Seasonal affective disorder is more similar to major depressive disorder in that symptoms may be just as severe, but signs only emerge during certain times of the year. Most people experience seasonal affective disorder during late fall or early winter, but it may also occur at the start of spring or summer. Symptoms may depend on the time of year. Those who experience fall and winter seasonal affective disorder may exhibit oversleeping, appetite changes (typically craving high-carb foods), weight gain, and tiredness and low energy. Meanwhile, those who experience spring and summer seasonal affective disorder may experience insomnia, poor appetite, weight loss, and anxiety.

What Are Antidepressants?

It’s important to understand exactly what antidepressants are, because they do not fit neatly in one category. Patients with depression may be prescribed one antidepressant, two antidepressants, or a combination of antidepressant(s) with other drugs, such as anti-anxiety medications. There are several types of antidepressants:

• Selective serotonin reuptake inhibitors (SSRIs): the most commonly prescribed antidepressants are SSRIs. They effectively treat moderate to severe depression and typically come with fewer side effects than other types of antidepressants. SSRIs work by increasing serotonin levels in the brain; they block the reabsorption of serotonin into neurons. The current SSRIs with Food and Drug Administration (FDA) approval include citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil, Pexeva), and sertraline (Zoloft). SSRIs are typically considered safe but may cause side effects including nausea, headache, blurred vision, dizziness, insomnia, and sexual dysfunction.
• Serotonin and norepinephrine reuptake inhibitors (SNRIs): SNRIs work similarly to SSRIs. In this case, they block the reabsorption of serotonin as well as norepinephrine in the brain. FDA-approved SNRIs include desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), and venlafaxine (Effexor XR). Some of the more common side effects associated with SNRIs are nausea, dry mouth, excessive sweating, headache, and dizziness; they may also cause loss of appetite and constipation.
• Norepinephrine and dopamine reuptake inhibitors (NDRIs): NDRIs block the transport of norepinephrine and dopamine in the brain. Currently, the only FDA-approved NDRI used to treat depression in the U.S. is bupropion (Wellbutrin).
• Tricyclic antidepressants: These are among the earliest antidepressants manufactured. Because they often come with a host of side effects, tricyclic antidepressants are not typically the first treatment to be prescribed unless others have been tried and failed. Tricyclic antidepressants include amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil), and nortriptyline (Pamelor). One of these may be an option for patients with treatment-resistant depression or depression with anxiety. It’s believed that tricyclic antidepressants work by blocking the reabsorption of serotonin and epinephrine. Side effects may include drowsiness, blurred vision, urine retention, drops in blood pressure when standing up from sitting, and more.
• Monoamine oxidase inhibitors (MAOIs): MAOIs were the first antidepressant to be made. Like tricyclic antidepressants, MAOIs are not often prescribed, in favor of newer treatments with fewer side effects. MAOIs work by preventing monoamine oxidase from removing norepinephrine, serotonin, and dopamine from the brain. Different MAOIs include isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Emsam), and tranylcypromine (Parnate). Selegiline can also be prescribed as a skin patch, which typically results in fewer side effects. MAOIs may cause dry mouth, insomnia, dizziness/lightheadedness, and nausea/diarrhea/constipation, among other side effects.

Who Is Taking Antidepressants?

According to the American Psychological Association (APA), more Americans than ever are taking antidepressants. In 2014, 12.7% of the population older than 12 was taking antidepressants. That’s up from 7.7% in 1999—a 64% increase. Antidepressant use increases with age, according to the APA data: nearly one in five adults older than 60 reported taking antidepressants in the past month. When broken down by age, 16.6% of adults between 40 and 59 years reported using antidepressants, compared to 7.8% in the 20–39 age group and 3.4% in the 12–19 years age group. Overall, women are twice as likely as men to be taking antidepressants, and the rate is higher for women than men in every age group.

Post-Antidepressant Effects: ‘A Common But Underappreciated Clinical Problem’

The potential benefits of antidepressants to treat depression—currently an incurable disease—may outshine the possible side effects, including those that may occur from medication termination. A study published in The Journal of the American Osteopathic Association discussed this possibility.

The researchers acknowledged that there are currently many unknowns when it comes to what happens when a person stops taking antidepressants. What research does exist focuses on two aspects: the drug’s initial primary biochemical effects, and the adaptive changes in synaptic function and plasticity that occur over the course of treatment.

The initial effects include increased availability of neurotransmitters resulting from inhibition of the synaptic reuptake of neurotransmitter amines. In SSRIs, this would refer to serotonin; in SNRIs and tricyclics, this would refer to serotonin and norepinephrine; and in buprion, this would refer to norepinephrine and dopamine. It only takes days of treatment for the biochemical changes to take place within the brain, although clinical differences in mood take two to six weeks to present themselves.

It is believed that antidepressant discontinuation symptoms occur when medication is stopped abruptly, which results in the unexpected loss of serotonin as well as temporary adaptive changes. The severity of these symptoms may vary from patient to patient, with some being significantly affected, although symptoms normally start to fade over the course of several weeks. It’s recommended that patients gradually be tapered off of antidepressants, rather than discontinuing immediately.

Symptoms of withdrawal following termination of antidepressants has been documented as early as the 1950s when the first antidepressants hit the market. These symptoms have been clinically classified as antidepressant discontinuation syndrome, to denote it from withdrawal, which is associated with an addictive drugs.

The authors explain, “Antidepressants are not considered to be addictive in the sense that users do not seek them to ‘get high’ but rather to alleviate symptoms of serious medical problems. However, with extended use, they can be notoriously difficult to quit because they can produce a state of physical dependence. Therefore, discontinuation can cause a group of symptoms that are very unpleasant and can lead patients to continue to seek the medications. The persistent use is not for a high but to alleviate symptoms of disease or to avoid unpleasant [antidepressant discontinuation symptoms].”

What Do Antidepressant Discontinuation Symptoms Look Like?

Symptoms usually manifest a few days after stopping treatment and typically continue for two weeks or longer. In most cases, symptoms occur in patients who abruptly stop taking antidepressants, but they may also occur in patients who slowly taper or miss a few doses of their medication. Factors that may increase the risk of symptoms include longer treatment duration and taking antidepressants with shorter half-lives for elimination, like paroxetine. Symptoms themselves also present differently from patient to patient, which could also change based on the drug class. Tricyclic antidepressants may be associated with similar symptoms to those of SSRIs but may also cause significant problems with balance and symptoms similar to Parkinson’s disease. SNRIs like venlafaxine may cause more severe symptoms than SSRIs. Meanwhile, more serious management may be needed for patients coming off of MAOIs, who may experience symptoms such like aggressiveness, cognitive impairment, or psychosis.

One strategy, created more than two decades ago, for identifying antidepressant discontinuation symptoms was to use the FINISH mnemonic, which stands for flulike symptoms, insomnia, nausea, imbalance, sensory disturbance (including shocklike “brain zaps”), and hyperarousal. The symptoms can be quantified using the Discontinuation Emergent Signs and Symptoms scale, also a longstanding tool. If these symptoms are not recognized, the patient is at risk for depressive relapse or treatment tolerance.

Depressive relapse symptoms are not the same as antidepressant discontinuation symptoms, with the former presenting several weeks after treatment termination. Patients with relapse symptoms typically present with gradual worsening of depression, insomnia, and psychomotor symptoms.

Antidepressants come with a possible risk of suicidal ideation, including suicidal thoughts—notably in young patients. They now come with a black-box warning from the FDA indicating this risk. The risk for suicidality is heightened not only while taking the medication but also during discontinuation. This risk is greater among patients taking medications with short half-lives.

Preventing Discontinuation Symptoms: What Can We Do?

Even tapering patients off of SSRIs may still come with the risk of discontinuation symptoms, but it seems to be the best strategy. Patients with mild symptoms can be managed with reassurance until the symptoms disappear, but in more severe cases, this could take longer. In this case, there are two options: (1) treat the symptoms, or (2) reinstate the medication and then follow a slow taper. In patients who do not respond well to tapering, a longer half-life option can be substituted for a short half-life one. Some patients may also benefit from behavior therapy and mindfulness-based therapies.

Tapering strategies are recommended based on anecdotal evidence, the study authors note here, and regimens have not been tested in systematic studies. Therefore, more concrete evidence is needed to make more definitive recommendations.