Negative Effects of Antidepressants: Is There a Dark Side?

Despite the widespread use of these prescription drugs (globally, this is a $14 billion business), antidepressants can have potentially negative effects on your health. (3) While they are life-saving for some, for others these medications can trigger side effects and symptoms that can disrupt normal routines, or they may be ineffective at alleviating depression. Keep reading to find out more about potential issues with antidepressants and learn how the Functional Medicine approach to psychiatry can help.

Antidepressants are life-saving for some; for others, they can cause negative side effects or fail to alleviate symptoms of depression. Check out this article for an updated look at antidepressants.

What Really Causes Depression (and What’s Wrong with the Chemical Imbalance Theory)?

Conventional medicine and the pharmaceutical companies have long maintained that depression is caused by an imbalance in brain chemicals. That’s why antidepressant meds are formulated to manipulate the levels of neurotransmitters in the brain. There are several classes of these drugs, including:

• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin and norepinephrine reuptake inhibitors (SNRIs)
• Tricyclic antidepressants
• Monoamine oxidase inhibitors (MAOIs)
• Atypical antidepressants

However, depression isn’t adequately characterized by “low serotonin” or “low epinephrine.” In fact, only about 25 percent of people diagnosed with depression have abnormally low levels of these neurotransmitters, while some have very high levels of them. (4) Although these facts don’t rule out chemical imbalance as a factor in depression, they do suggest that it’s not the only one. 

In reality, depression may be a symptom of one or more underlying issues. I discussed in a previous article how inflammation may be at the root of many cases of depression, (5) but other causes of mental health issues can include:

• Pathogens
• Faulty gut–brain axis signaling (6)
• Gut dysbiosis and/or intestinal permeability (6, 7)
• Trauma (8)
• Loneliness
• HPA-axis dysregulation (9, 10)
• Nutritional deficiencies (11)

Any treatment plan that fails to address these underlying causes isn’t likely to be effective for someone who is suffering from depression. That’s why it’s so important to move beyond the default chemical imbalance explanation and understand what’s really driving the condition.

Antidepressants May Not Be as Effective as You Might Think

Important disclaimer: If you are currently taking an antidepressant, do not stop abruptly and do not taper off the meds without the guidance and support of your healthcare providers. I’ll discuss more about how to taper off of medication below, but it is crucial that you do not undertake any steps without consulting closely with your doctor.

Given the hype surrounding antidepressants, you may be surprised to learn initial treatment is effective at mitigating symptoms only about half the time. (12) Even after trying several treatments, up to 30 percent of those with depression never achieve remission. (13)

While a large meta-analysis published in 2018 in the prestigious journal, The Lancet, states that all antidepressants perform significantly better than placebo, (14) critics have pointed out that these differences are small and not clinically relevant. (15) The majority of high-quality research studies have shown that SSRIs have no benefit over placebo for mild and moderate depression. (16, 17, 18, 19)

One Problem: Clinical Trial Groups Are Not Representative of Real-World People

One major issue with the research on antidepressant efficacy is the selection process of clinical trial group participants. Because the selection process is not standardized or subject to any federal guidelines, patients with milder forms of depression, chronic depression, or other psychiatric or medical conditions in addition to short-term depression are excluded from studies. (20) In some cases, less than 20 percent of people who apply to be part of an antidepressant efficacy trial do not meet the requirements, meaning that study groups are not representative of a real-world population. (21)

Here is why such exclusions matter: In a normal, clinical setting, many patients with depression have other illnesses, such as diabetes, chronic fatigue syndrome, or irritable bowel syndrome. It’s not unusual for them to have anxiety and insomnia, as well. In fact, it’s quite possible that a person with depression might be suffering from other conditions that are either contributing to or caused by their illness. 

One study looked at the efficacy of antidepressants in those who did not meet phase III inclusion criteria (phase III clinical trials include and exclude participants based on stringent criteria that would actually exclude the majority of people who take the drugs in real life). Among participants who would not qualify under phase III criteria, researchers found that their outcomes were, unsurprisingly, much worse than those who did qualify for the trials. (22)

It’s important to note the wide variability in individual response to antidepressants. SSRIs and other antidepressants can be game changers for many people, but the reported average response rate in clinical trials won’t shed any light on how one person reacts to a medication versus another individual. However, what’s clear is that these drugs are not a panacea for global mental illness, and that this is a complex topic.

Two Drug-Free Treatments That Can Be as Effective as or More Effective Than Antidepressants

Another important detail to note is that non-pharmaceutical treatments can be as effective or even more effective than antidepressants. Evidence shows promising results for psychotherapy and exercise as effective interventions.

1. Psychotherapy

Substantial evidence demonstrates that psychotherapies, like cognitive-behavioral therapy (CBT), are just as effective as antidepressants for long-term maintenance, for first-line treatment, and even for treatment-resistant depression. (23, 24, 25, 26, 27) In some cases, psychotherapy has actually outperformed antidepressants or added additional benefit to medication. (28, 29, 30)

CBT also might reduce the risk of depression relapse, which is very common. (31, 32) If you’ve had depression once, your risk of developing depression again is about 50 percent. If you’ve had two episodes, you’re 80 percent likely to relapse. (33, 34)

CBT may offer unique skills for preventing relapse. As one review from 2017 states: (35)

“Residual symptoms and relapse risk would decrease if patients in partial or full remission can learn, first, to be more aware of negative thoughts and feelings at times of potential relapse/recurrence, and, second, to respond to those thoughts and feelings in ways that allow them to disengage from ruminative depressive processing.”

2. Exercise

Exercise may be powerful for preventing and alleviating depression. Exercise has mood-boosting effects and can decrease inflammation, improve vagal tone, and modulate neurotransmitters, all of which can help decrease depressive symptoms. (36, 37)

Although not all studies are in agreement, (38) many clinical trials and meta-analyses have determined that exercise can be helpful as an adjunct to antidepressants, or even by itself. (39, 40, 41, 42) Of note, people who already have depression may not have enough motivation and energy to start an exercise regimen, especially on their own. However, perhaps surprisingly, drop-out rates among those who participate in exercise groups generally aren’t higher than drop-out rates for other types of treatments. (43) As exercise boasts numerous health benefits beyond mood improvement, it’s worth considering.

Negative Side Effects of Antidepressants

Side effects are quite common for people who take antidepressants. More than half of those beginning an antidepressant have one of the more common side effects: (44)

• Nausea
• Decreased libido (very common, especially among men: up to 40 percent taking antidepressants experience this side effect)
• Tiredness and/or insomnia
• Dry mouth
• Constipation
• Dizziness
• Anxiety
• Weight gain
• Sweating

While some of the side effects listed above are manageable and won’t cause serious or long-term health complications, others, such as weight gain or anxiety, may—especially if they persist.

Jitteriness Syndrome, Anxiety, and Akathisia

In the first few months of beginning an antidepressant, “jitteriness syndrome” and anxiety are common side effects. Up to one in four people will experience jitteriness syndrome, and studies have reported a wide range of anxiety incidence related to beginning antidepressants, from 4 to 65 percent. (45) Frequently, those who show anxiety are then prescribed another medication, like a benzodiazepine, with its own risks.

In rare cases, a particular type of severe agitation called akathisia may occur. (46) Akathisia has been shown to increase aggression, violent behavior, and suicide.

Suicide

In 2004, the U.S. Food and Drug Administration (FDA) issued a black-box warning that antidepressants may increase suicidal ideation and attempts in children. A couple years later, they extended the warning to include those up to age 25 and also stated that patients of all ages should be monitored for suicidal ideation, plans, and/or attempts. (47)

The studies surrounding suicide and antidepressants are mixed. Some studies have shown higher suicidal behavior in adults and children (48, 49, 50, 51), while others haven’t. (52, 53) Published FDA investigations state that those under age 25 taking antidepressants have about twice the rate of suicidal behavior compared to those taking placebo. (54, 55) SSRI users might be more at risk than users of other classes of antidepressants, and suicide risk seems highest in the first month starting and stopping the meds. (59)

In general, post-2000 studies show lower rates of suicide among antidepressant trials, despite the fact that suicides have increased since then. (60) Some claim that the earlier studies were flawed or that suicidal ideation is better monitored during trials, but others say that the lower rates in recent studies are due to “enhanced screening procedures and effective exclusion of suicidal patients in clinical trials for depression.” (61) To me, that explanation is far from reassuring. The fact remains that individuals who are actually suicidal will be prescribed antidepressants, but robust studies looking at the efficacy of meds in this population just don’t exist.

Other Side Effects

Other side effects can occur with antidepressants, though some still aren’t well-characterized and many are rare: (62, 63, 64, 65)

• Numbness or anti-motivational syndrome
• Interactions with other drugs (ibuprofen and SSRIs don’t mix, for example) (66)
• Depletion of beneficial gut bacteria (antidepressants have antimicrobial properties)
• Osteoporosis
• Cardiovascular issues
• Personality changes
• Gastrointestinal symptoms including diarrhea, gastrointestinal bleeding, and dyspepsia (for which antacids may be prescribed)
• Birth defects
• Liver injury (very rare)

As with any medication, adequate risks/benefits must be taken into consideration. Even when experiencing side effects, stopping antidepressants needs to be done under the guidance of a healthcare provider.

Weaning off Antidepressants Is Difficult

Antidepressants were intended for short-term treatment of depression, but in actuality, people are taking them continuously for years on end. Half of American antidepressant users have been on them for more than five years, though long-term data on effectiveness and safety are sparse. (67) A review of 14 studies on long-term depression treatment indicated that patients who were treated with drugs fared no better than those who weren’t treated with drugs long-term. (68) In another study of people with depression and on antidepressants for over two years, the patients who did not take drugs after remission had a lower rate of remission compared to those who did. (69)

A big reason that people stay on antidepressants long-term is simply this: Withdrawal symptoms make it very difficult to stop. In a systematic review of patients trying to wean off antidepressants, 46 percent of the participants described withdrawal effects as “severe.” (70) Common withdrawal symptoms include:

• Dizziness
• Fatigue
• Irritability
• Confusion
• Insomnia
• Relapse of depression

Slowly Tapering off Antidepressants Is More Successful Than Current Recommendations

One major problem is that patients are weaning off antidepressants too quickly—often at their doctors’ orders. The prevailing recommendation is to wean off completely in a period of two to four weeks. (71) However, evidence demonstrates that decreasing the dose over a much longer period of time results in much lower rates of side effects and results in more consistent levels of neurotransmitters, as imaged by positron emission tomography scans. (72) Several studies have shown the benefits of tapering more slowly (73, 74, 75) including one study that found that patients who slowly came off an SSRI over an average of 38 weeks had only a 6 percent chance of withdrawal syndrome, compared to a 78 percent chance in the group who stopped quickly. (75)

Tapering slowly may take longer, but it’s much more likely to be effective. (76)

The Functional Psychiatry Solution

Do antidepressants have a place in treating depression? As I said above, for some people, they can be game changers. But they don’t work for everyone, and they will not address any underlying issues that are causing or contributing to depressive symptoms.

A better approach to depression and other mental health issues is the functional psychiatry solution, which treats the root cause of a disorder rather than masking symptoms with prescription drugs.

Using a holistic approach, a functional psychiatry approach to depression may involve interventions such as:

• Metabolic testing
• Psychotherapy
• Dietary interventions
• Stress management
• And more

By addressing the true underlying causes of depression, the functional psychiatry approach can improve long-term outcomes for people with depression, giving them relief from their symptoms without the addition of any negative effects of antidepressants.