SSRIs impair the brain’s reward learning system, new research finds. Celeste McGovern looks at safe ways to get off antidepressants and alternative treatments.
Among the problems plaguing the profession are soaring mental health statistics, patient recovery rates that have flatlined for decades, and a growing stack of evidence that the primary tools of the trade—psychoactive drugs including super-selling antidepressants—don’t work so well and are linked to an expanding litany of damaging side-effects that are increasingly hard to ignore.
Depression remains the number one cause of disability in the United States, as it is across the Western world. Younger adults and adolescents are most affected, and increasingly at younger ages; suicide is now the second leading cause of death for youths aged 10 to 19.1 Mental illness is the leading cause of disability in children, outpacing physical disabilities like cerebral palsy or Down syndrome. A staggering 2.7 million American children ages 3–17 received a depression diagnosis in 2016–2019.2
By far the biggest consumers of antidepressants are women, however. More than 17 percent of American women had taken antidepressants in the past month in 2015–2018, according to the CDC, and for women over the age of 60, that number rose to nearly one in four (24.3 percent).3
Doctors used to prescribe antidepressants for people with rare “melancholia” back in the 1960s and ’70s, but the old drugs, like tricyclics, had grim side-effects and their use was limited.
In the late ’80s, a new line of antidepressants called SSRIs (selective serotonin reuptake inhibitors) was approved by the US Food and Drug Administration. SSRIs block the reuptake of the chemical messenger serotonin into neurons and thereby are believed to make more serotonin available to improve transmission of messages between neurons.4
The first of the SSRIs, Prozac, was rolled out as a new “magic bullet” for “mood disorders,” and prescriptions for antidepressant drugs climbed year on year until now one in six Americans is taking an antidepressant and one quarter of those people have been taking the drugs for a decade or more.3
With Prozac’s mass success, Pfizer launched its own antidepressant Zoloft in 1992 and was the first to begin claiming in public advertising—without a shred of data to support the theory—that its drugs were correcting a “chemical imbalance in the brain.”
Pharma told marketing, who told psychiatrists and general practitioners, who told patients who were sad or despondent they must have a deficiency of serotonin, a neurotransmitter that is crucial to maintaining a sense of wellbeing. They presented it like a deficiency of thyroid hormone, as correctible with antidepressants as diabetes is with insulin.
Never mind that there was no data for the “chemical imbalance” theory. For the past three decades, that chemical imbalance mantra was sold to consumers through television and magazine mass marketing as prescriptions soared. Only in the past few years, now that the theory has been repeatedly debunked, has the chemical imbalance campaign abated, though some doctors still cling to it.
In February, STAT News published an investigative piece revealing that another staple of the mental health system—a nine-item questionnaire used to diagnose depression called the PHQ-9—was never based on any science, or even on clinical experience. Instead, it was the brainchild of one of Pfizer’s marketing gurus, part of a campaign to increase Zoloft use.
“It wouldn’t have happened if it wasn’t for me,” Howard Kroplick, now 73 years old, said of the test that is used extensively around the globe to try to pick out depression in patients, whether they complain of it or not. The assessment has been cited in more than 11,000 research papers.5
With such successful marketing, from the mid-1990s on, the umbrella for depression began to widen until it covered the “mildly depressed” and those merely trying to boost their job performance or use the drugs as “personality enhancers.” At the same time, Freudian psychoanalysis was in a free fall out of fashion, and those who might have been given “talk therapy” were instead given pills.6
While an imbalance of neurotransmitters has been scientifically ruled out as the underlying cause of depression, it does appear to be the effect of antidepressant treatment with SSRIs. As Robert Whitaker wrote in his groundbreaking book Anatomy of an Epidemic (Crown, 2011), “Once a person is put on a psychiatric medication, which, in one manner or another, throws a wrench into the usual mechanics of a neuronal pathway, his or her brain begins to function . . . abnormally.”
Abnormal function from antidepressants was confirmed most recently in a study conducted by University of Cambridge and University of Copenhagen researchers. They looked at the effects of an SSRI antidepressant (escitalopram) on a group of 66 healthy volunteers.
One of the well-documented side-effects of SSRIs, reported by 40–60 percent of users, is emotional “blunting,” or feeling deadened to pleasure.
For the experiment, the group was split in two—32 volunteers were given escitalopram (Lexapro or Cipralex), and the other 34 were given a placebo for at least 21 days. Both groups completed a series of questionnaires and tests assessing cognitive functions including learning, inhibition, executive function, reinforcement behavior and decision-making.
In the short time frame of the study, the researchers reported no effects on most cognitive functions, including attention and memory. However, the major new finding was that after “treatment,” the drug group scored significantly lower on “reinforcement sensitivity,” a measure of learning from feedback on our actions in the environment.
To assess this function, study volunteers were shown two stimuli, A and B. If they chose A, they would receive a reward four out of five times. But if they chose B, they got the reward only one out of five times. Participants were not told this rule but had to learn it on their own. During the experiment, the rewards for A and B would switch, and participants would need to recognize the change and adjust their decisions accordingly.
Volunteers taking the antidepressants were much less likely to base their decisions on the positive and negative feedback than volunteers on the placebo, suggesting the drug affected their ability to detect rewards—or success.
The study also confirmed another common side-effect of antidepressants: those on the drugs reported having trouble reaching orgasm during sex.
“Emotional blunting is a common side effect of SSRI antidepressants,” said Barbara Sahakian, a psychiatry professor at the University of Cambridge and one of the study’s authors. “In a way, this may be in part how they work—they take away some of the emotional pain that people who experience depression feel, but, unfortunately, it seems that they also take away some of the enjoyment. From our study, we can now see that this is because they become less sensitive to rewards, which provide important feedback.”7
And without this key cognitive function, wouldn’t the drugs lead to a greater sense of failure and pessimism?
Reward recognition is only one of a litany of side-effects of antidepressants that have taken the mental health profession a long time to acknowledge, however. Sexual dysfunction is high on the list as well. So are feeling agitated or anxious, sweating profusely and feeling nauseated. Ironically, suicide and suicidal ideation also make the list.
In 2004, the US FDA issued a black-box warning on all antidepressants after placebo-controlled trials found they increased the risk of suicidal thoughts and behaviors among children and adolescents. These side-effects were most noticeable within the first nine days after starting the drugs.8
A 2016 review of 13 drug trials published in the Journal of the Royal Society of Medicine explored suicidality among adults taking antidepressants. It was even more damning.
“We found that antidepressants double the risk of suicidality and violence, and it is particularly interesting that the volunteers in the studies we reviewed were healthy adults with no signs of a mental disorder,” said the researchers. Evidence pointed to the drugs making healthy people suicidal.
What’s more, the researchers warned, “There can be little doubt that we underestimated the harms of antidepressants.” They blamed drug manufacturers for underreporting serious harms by “simply omitting them from the reports, by calling them something else or by committing scientific misconduct.”
They pointed to the case of a healthy 19-year-old student who volunteered in an Eli Lilly trial of its antidepressant duloxetine to help pay her college tuition and later hanged herself in a laboratory run by the company.
“It turned out that missing in the FDA’s files was any record of the college student and at least four other volunteers known to have committed suicide, and Lilly admitted that it had never made public at least two of those deaths,” according to the paper.9
Recently, some psychiatrists have called for the FDA to delete its Black Box suicide warning from antidepressants, complaining that it steers people away from the drugs, but a 2020 review of the science said the warning is “firmly rooted in solid data.”10
Another side-effect of antidepressants is “withdrawal syndrome.” Mainstream medicine denied for decades that the drugs are addictive, but thousands of patients describing their debilitating withdrawal symptoms in online forums have forced professional discussion of the dependence problem.
A new article published March 2023 in the British Journal of General Practice advises doctors that more than half of patients who stop taking SSRI antidepressants will experience severe and long-lasting withdrawal symptoms, including suicidality.11
According to researchers from the Brighton and Sussex Medical School, “Psychological symptoms include irritability, anxiety, low mood, sleep disturbance, suicidal ideation, and hallucinations.
“Physical manifestations include dizziness, flu-like illness, palpitations, headaches, muscle pain and tremors, sweating, gastrointestinal symptoms (nausea, diarrhea), and sensory disturbances (‘electric shocks,’ ‘brain zaps’).”
This litany of other “distressing” adverse effects includes some symptoms that make it hard to tell SSRI antidepressant withdrawal from a relapse into depression itself.
Withdrawal and depression have a lot of shared symptoms, and many doctors don’t distinguish between the two. These are some strategies to differentiate withdrawal from relapse:
Identify whether you are experiencing physical symptoms of withdrawal that are not likely characteristics of depression, such as sensory disturbances, muscle pain or nausea.
Think about when symptoms began. Withdrawal typically begins within days of stopping antidepressants (except in the case of fluoxetine, which has a longer half-life), whereas relapse into depression takes weeks to months.
Does reintroducing the drug rapidly reduce the intensity of the symptoms? If so, it is more likely withdrawal syndrome than depression or anxiety relapse since these usually take weeks to improve with antidepressants.
Getting off SSRIs is not straightforward, either. Decreases to smaller doses cause larger changes to neurotransmission, so traditional linear dose reductions (for example, reducing sertraline by 50‑mg increments) can cause increasingly large (or hyperbolic) changes and more severe symptoms, according to the Brighton and Sussex researchers: “This explains why some patients may tolerate the early stages of their taper but towards the end, at lower doses, they experience withdrawal symptoms.”
Instead, as recommended by the National Institute for Health and Care Excellence (NICE) and the Royal College of Psychiatrists, they advise a “proportionate taper” to reduce symptoms. In this method, a proportion of the previous dose (say, 25 percent) is cut in succession, using liquid dosing where necessary.
“To prevent withdrawal symptoms, tapering should take place over a long period of time, spanning months, or even years. SSRIs with shorter half-lives, such as paroxetine and venlafaxine, require a longer taper.”
How to taper off
The researchers from Brighton and Sussex Medical School suggest the following approach to gradually stop taking SSRIs.
While more light is being shone on the troubles with antidepressants, what to do to get out of the black hole? If a chemical imbalance is not at the heart of depression, what is? And if antidepressant drugs don’t help in the long run, what does?
Among disillusioned practitioners, there has been a pendulum shift recently back to psychoanalysis, with renewed acceptance of at least some Freudian ideas of repression and unconscious guilt. A growing number of therapists are also addressing childhood trauma that people may unconsciously repeat in different experiences until they confront it and slay it.
Even these practitioners recognize the physiological aspects of depression, however. Grief, sadness, guilt, remorse and disappointment create changes in our physiology, which can create a negative feedback loop in our thinking.
In 2015, Canadian researchers used positron emission tomography (PET) to scan the brains of 20 patients with depression and compare them to 20 healthy control participants. They paid special attention to the activation of microglial cells that play a critical role in the immune system’s inflammatory responses.
They discovered significant inflammation in the brains of people with depression, which was most severe among participants with the most severe depression. People who were diagnosed with clinical depression had about 30 percent more inflammation in their brains than the healthy controls did.12
Since then, many studies have confirmed the role of inflammation in mental health. Addressing issues related to inflammation is the forte of integrative psychiatrists like James Greenblatt.
“I am not interested in pinpointing the blame for your depression on your past, your parents or on you,” says Greenblatt, an assistant clinical professor of psychiatry at Tufts University School of Medicine and Dartmouth College Geisel School of Medicine and author of Integrative Medicine for Depression: A Breakthrough Treatment Plan That Eliminates Depression Naturally (Friesen Press, 2019). “The health of the brain, or what we might call the mind, depends directly on the health of the body.”
To that end, Greenblatt takes a functional medicine approach to mental illness, and on his Psychiatry Redefined education platform, he trains other practitioners to do the same. He looks at the individuals’ markers of inflammation and sources that could be fueling an inflammatory fire, from amino acid or vitamin deficiencies to hormone imbalances to microbial infections or imbalances.
Here are a few of the more common deficiencies that can cause depression and ways to correct them. While supplements are helpful, many of these can be remedied with food sources.
Thyroid and other hormones
Though depression and anxiety are well-documented side-effects of low thyroid hormone, depressed people rarely have their thyroid hormone levels checked, though Dr Greenblatt believes this should be a fundamental first step.
Thyroid tests should measure basal body temperature, serum levels of thyroid-stimulating hormone (TSH), and free T3 and T4 levels. Thyroid hormone should be supplemented in its natural form rather than with synthetic hormones, in an amount based on the test results.
Dehydroepiandrosterone (DHEA) is a hormone produced by the adrenal glands that wanes after midlife. A 2005 double-blind, placebo-controlled, crossover study published in the Archives of General Psychiatry tested six weeks of DHEA therapy, 90 mg per day for three weeks and 450 mg per day for three weeks, against six weeks of placebo and reported a 50 percent reduction in depression scores in the treatment group and improved sexual function.
It concluded that DHEA is “an effective treatment for midlife-onset major and minor depression.”13
Zinc
Zinc is abundant in the central nervous system and critical to hundreds of enzymatic reactions that fuel a wide range of functions, from DNA synthesis and digestion to immune system function. A 2013 review of 17 studies found lower levels of zinc in depressed people than in those without depression.14
When Dr Greenblatt saw a 28-year-old patient named Gabi for the first time, she had a 14-year history of depression and was taking three different antidepressant medications to improve it.
Gabi had white spots on her fingernails, one sign of low zinc. Blood testing showed a very low reading for alkaline phosphatase, a liver enzyme that needs zinc for its production, and in a taste test, liquid zinc tasted like water to her, indicating Gabi was deficient in the mineral.
Within a year after Dr Greenblatt had her begin taking supplemental zinc, she was off all antidepressants and depression free.
Daily dosage: Up to 40 mg per day for adults, or a dosage based on the results of a taste test.
Zinc taste test
Dr James Greenblatt has found over decades of integrative psychiatry practice that the most reliable way to test zinc levels is a simple taste test, based on the premise that taste is reliant on having adequate zinc levels in the body.
Do not eat, drink or smoke for at least an hour before the test so that no competing tastes will interfere with the results.
Bring an unflavored 1 percent zinc sulfate solution to room temperature for at least two hours before using it to test. Take a sip (5 to 10 mL) of the solution and hold or swirl it in the mouth for 10 seconds before spitting or swallowing.
For people in groups 1 and 2, Dr Greenblatt recommends supplementing 30 mg of zinc up to three times a day, not exceeding 90 mg/day in total. For those in groups 3 and 4, a multivitamin containing at least 15 mg of zinc is enough to maintain sufficient levels.
Magnesium
Deficiencies of magnesium have been linked to nervousness, anxiety, insomnia and depression. Some case reports have described individuals taking 125–300 mg of magnesium as magnesium glycinate and magnesium taurinate with meals three times a day and at bedtime and showing rapid recovery from major depression.15
A 2017 review of magnesium’s role in neurological disorders similarly found that participants consuming just 248 mg of magnesium chloride per day for six weeks showed marked improvements on depression scores compared to those receiving no treatment. The effects could be seen within two weeks.16
Daily dosage: For adults, up to 600 mg of elemental magnesium from magnesium chloride, glycinate or taurinate. If you experience diarrhea, low blood pressure or irregular heartbeat, you may be taking too much. Magnesium glutamate and aspartate are not recommended as they can worsen depression and other neurological symptoms.
B vitamins
Vitamins B1 (thiamine), B3 (niacin), B6 (pyridoxine), B9 (folate) and B12 (cobalamin) are essential for neuronal function, and deficiencies have been linked to depression in multiple studies.17
B1: Thiamine is essential for glucose uptake in the brain, and too little of it can lead to mood disorders and fatigue. A landmark 2013 study tested 1,587 Chinese adults between 50 and 70 years old and found that 28.2 percent were deficient in thiamine.
More importantly, the researchers found that lower concentrations of thiamine were associated with higher odds of having depressive symptoms, independent of other potential risk factors for depression. An earlier British study had found that 46 percent of nursing home residents aged 67–92 had low thiamine levels, compared with only 13 percent of participants aged 19–37.18
B9: Folate is critical in brain development, and deficiency in the vitamin has been linked to depression since the 1960s. In one trial, about 68 percent of patients on antidepressants given supplemental doses of L-methylfolate saw their depression improve in three months, and an astounding 45.7 percent achieved full remission from depression within 95 days.19
B12: According to one study, older women who had vitamin B12 deficiency were about twice as likely to be severely depressed as nondeficient older women.20
Other studies found people, especially vegetarians, who developed mental health issues including depression had low vitamin B12 readings. However, the studies also found they rapidly recovered when they supplemented
the vitamin.21
Daily dosage: Thiamine, 0.33 mg for every 1,000 calories in food each day, up to 300 mg per day. Folate, 3 to 15 mg of L-methylfolate per day. Vitamin B12, up to 1 mg as methyl cobalamin and adenosylcobalamin.
Pyrroles
Pyrroles are metabolites that are normally excreted in urine. A urine Kryptopyrrole test may reveal high levels of the compounds, which bind to vitamin B6 and zinc, depleting them faster and preventing their use in the brain.
The resulting deficiency can lead to symptoms including anxiety, mood swings, severe inner tension, depression and psychosis.
Daily dosage: A urine test result of >15 mcg/dL can be treated with 100 to 400 mg per day of vitamin B6 (as pyridoxyl-5-phosphate) and 25 to 100 mg per day of zinc as zinc picolinate.
Running
A 2020 review of 116 studies looked at the association between running and mental health. It concluded that “running has important positive implications for mental health, particularly for depression and anxiety disorders.”22
“Runner’s high,” often described as fueled by a rush of endorphins, is more likely fueled by the release of endocannabinoids into the bloodstream triggered by high-intensity and endurance running, according to recent research. Endocannabinoids are mood-boosting neuromodulators that produce short-term effects including reduced anxiety and feelings of calm.23
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Alicia VanOrman and Beth Jarosz, “Suicide Replaces Homicide as Second-Leading Cause of Death among US Teenagers,” June 9, 2016, prb.org; CDC, “Facts about Suicide,” Oct 24, 2022, cdc.gov |
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CDC, “Anxiety and Depression in Children: Get the Facts,” Mar 8, 2023, cdc.gov |
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Debra J. Brody and Qiuping Gu, NCHS Data Brief No. 377, Sept 2020, cdc.gov |
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Mayo Clinic, “Selective Serotonin Reuptake Inhibitors (SSRIs),” Sept 17, 2019, mayoclinic.org |
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Olivia Greenblatt, “How a Depression Test Devised by a Zoloft Marketer Became a Crutch for a Failing Mental Health System,” Feb 21, 2023, statnews.com; Hilary Brueck, “The 9-Question Survey Many Doctors Use to Diagnose Depression Was Actually Created by an Antidepressant Manufacturer,” Feb 23, 2023, insider.com |
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Mark L. Ruffalo, “The Story of Prozac: A Landmark Drug in Psychiatry,” Mar 1, 2020, psychologytoday.com |
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