Antidepressant Knife

This mini-booklet reviews the relative effectiveness, safety and harms of antidepressant drugs.

How is the information about psychiatric drugs on this page different from what’s provided by other online resources, and why should I read it?

Inner Compass Initiative has developed these informational pages because many descriptions of the safety and effectiveness of psychiatric drugs that are provided by popular online medical, psychiatric and mental health websites are often brief, vague, and more promotional than factual. (For an examination of some of the reasons why this is the case, please read ICI’s “How Psychiatric Drugs are Researched and Marketed".) We believe that, when trying to make serious, potentially life-changing decisions about whether to take or discontinue psychiatric drugs, people deserve a fairer opportunity to properly understand and evaluate the potential risks and benefits, and thereby be empowered to make informed choices. Our articles will take you more time to read because they provide more detailed information than most of the overviews you’ll read elsewhere – but isn’t your health worth the investment?

If you notice an error, broken link or needed update, please contact us. Click here to learn more about Inner Compass Initiative.

Why do Inner Compass Initiative’s reviews of safety and effectiveness focus mainly on the FDA-approved drug labels?

Inner Compass Initiative’s mini-booklets about the six main classes of psychiatric drugs do not review all of the scientific research about these drugs. That would be an extremely ambitious effort that could easily fill an entire book for each drug class, after which even the most neutral team of researchers could still be accused of “cherry picking” evidence from tens of thousands of available studies. We have taken a different approach. We’ve focused mainly on reporting and clarifying what is arguably the single most important body of evidence: The evidence that drug companies themselves provided to government health regulators in order to try to establish evidence that their drugs are safe and effective.

If a pharmaceutical company wishes to market a prescription drug for a specific use in the United States, the company is legally required to provide scientific evidence in support of its application to the Food and Drug Administration (FDA). If the drug is approved by the FDA, this evidence is then summarized in the official “drug label”. The information pamphlets for consumers that come with prescription drugs are often unregulated, general information about the drug or just a brief collection of highlights from the drug label. In its complete form, the official drug label can be ten to fifty pages or longer in length, and includes the “Full Prescribing Information” and “Medication Guide” that are intended to inform physicians, psychiatrists, pharmacists and others about the most important scientific evidence relating to the safety and effectiveness of that drug. Since the drug labels are generally based on evidence provided to the FDA by the drug companies themselves, and are developed in collaboration between the drug companies and FDA, they tend to be strongly biased in favor of the drugs. Yet even with this bias, we at Inner Compass Initiative believe that most readers, like us, will find much of the information in them to be enlightening, surprising, concerning and even at times shocking – and nothing if not helpful for making more informed decisions weighing the potential risks and benefits of psychiatric drugs. So in creating our mini-booklets, we distilled the contents of a representative sampling of drug labels from each major class of psychiatric drugs -- supplemented at times with information from related scientific studies and the FDA's own medical reviews. (Also included are some general Q&As about key ideas in psychiatric science such as safety, effectiveness, and drug dependence, which apply to essentially all psychiatric drugs and are duplicated across the mini-booklets.)

Still, we urge anyone who is considering or already taking any psychiatric drug to read the official drug label in full. These are freely available online at a variety of commercial websites, but the most reliably up-to-date sources are those run by the federal government such as DailyMed. (Instructions and links for obtaining and understanding drug labels and related information such as FDA medical reviews can be found in “The Withdrawal Project's Guide to the FDA-approved Drug Labels”.) We also strongly recommend doing additional self-directed research, such as examining the FDA’s internal medical reviews, using online tools for searching scientific journal articles, perusing Inner Compass Initiative’s “Resources” section, conferring with people who’ve taken the drug, and consulting with well-informed, supportive prescribers or pharmacists. Choice is only truly meaningful – and truly possible – when it is informed.

What are "antidepressants" and what are they prescribed for?

“Antidepressant” is a marketing name that is applied to a wide range of chemically different classes of drugs that act on the body and brain in different ways. These drugs include:

  • Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, paroxetine, escitalopram and citalopram (e.g. U.S. brand names Prozac, Zoloft, Paxil, Lexapro, and Celexa).
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine, desvenlafaxine and venlafaxine (e.g. Cymbalta, Pristiq and Effexor).
  • Tricyclics (TCAs) such as clomipramine, amitriptyline and imipramine (e.g. Anafranil, Elavil and Tofranil).
  • Monoamine oxidase inhibitors (MAOIs) such as phenelzine and isocarboxazid (e.g. Nardil and Marplan).
  • Tetracyclics (TeCAs) such as mirtazapine (e.g. Remeron).
  • Atypicals such as bupropion (e.g. Wellbutrin).
  • Norepinephrine reuptake inhibitors (NRIs), serotonin antagonists and reuptake inhibitors (SARIs), serotonin modulators and stimulators (SMSs) and many more.

Antidepressants are prescribed to treat people diagnosed with a wide variety of depressive, anxiety, obsessive compulsive, eating, post-traumatic stress, and attention disorders, problems sleeping, and many other conditions. The U.S. Food and Drug Administration (FDA) has not approved most of these drugs to be used to treat people diagnosed with most of these conditions, but some physicians and psychiatrists prescribe the drugs for these conditions “off-label”. (When a physician prescribes a drug for a use that has not been approved by the FDA and is not listed on the official drug label, the physician is prescribing “off-label”.)

Since there are so many widely different types of antidepressants, this article provides information about antidepressants generally, but examines in more detail only the widely used SSRI and SNRI antidepressants.

How do antidepressants work?

Notably, the answer to the above question is, in some important ways, similar for all of the major classes of psychiatric drugs: We don't truly know. It can be misleading to talk about how antidepressants work, because the word “work” implies that the drugs have a well-understood effect on a discrete area or pathway in the brain that’s involved in depression or anxiety, or cure an abnormal biological condition, disease or disorder. For many it can be surprising to hear because we’re so often led to believe otherwise, but there is still today no known, biologically detectable mental disorder or discrete area or pathway in the brain that antidepressant drugs treat or cure. (For more information, read ICI’s “How Mental Disorders are Diagnosed” and “How Psychiatric Drugs are Researched and Marketed”.)

Antidepressants are psychoactive chemicals that act on the brain in a variety of ways. It is common for popular medical websites, news media, non-profit organizations, and even medical professionals to state that antidepressant drugs work by “increasing levels of serotonin in the brain” or “by slowing or blocking the sending neuron from taking back the released serotonin”.

This is certainly part of what antidepressants do, but the research is in fact unclear about whether or how this particular drug action affects people’s moods or experiences. Indeed, the U.S. Food and Drug Administration (FDA) and pharmaceutical manufacturers have developed medically definitive descriptions of the mechanisms of action for every antidepressant that is approved for use in the United States. These can normally be found in the “Clinical Pharmacology” section of the official drug label. (Instructions and links for obtaining and understanding drug labels can be found in “The Withdrawal Project's Guide to the FDA-approved Drug Labels”.) According to these explanations, the biological mechanisms by which any antidepressant drugs might affect some people diagnosed with mental disorders in “therapeutic” ways are “unknown”.

One persistently popular hypothesis or belief about how SSRI antidepressants work tends to focus on one aspect of how these drugs seem to affect the neurotransmitter serotonin – but the “low-serotonin theory of depression” has never been proven. Meanwhile, it has become clear that all antidepressants directly or indirectly disrupt, impair, enhance, mimic or otherwise alter the activities of a number of major neurotransmitters, including serotonin, norepinephrine, dopamine, histamine and acetylcholine.

Neurotransmitters are chemical messengers that play essential roles in all of the basic communications and functional systems in the brain and body. Serotonin, for example, is known to be involved in appetite, wakefulness and attention, body temperature regulation, emotions and moods, sensory perceptions, sleep and more. Norepinephrine is also involved in alertness, arousal, wakefulness, sensory perceptions and memory, and is furthermore central to the functioning of the sympathetic nervous system which includes eyes, heart, lungs, liver, stomach, kidneys, muscles, skin, and the adrenal gland. Not surprisingly, then, altering the activities of any of these neurotransmitters with drugs can have a wide range of effects on many different aspects of the brain and body. In addition, as the body adjusts to the presence of an antidepressant drug over long periods of time, very different effects can often develop. For these reasons, how any antidepressant drugs act on the brain and body are not well or fully understood.

However, when we understand that antidepressants are not known to specifically target or treat any detectable, underlying biological disease, it actually becomes easier to understand how they may work and why the very same drugs can often be prescribed to people who’ve been diagnosed with so many different kinds of mental disorders such as Major Depressive Disorder, General Anxiety Disorder, Post-traumatic Stress Disorder, Obsessive-Compulsive Disorder, sleep problems, traumatic brain injuries and more. Essentially, antidepressants are psychoactive drugs that some people can find helpful in a similar way to how some people find other mild-to-strong psychoactive drugs like coffee, alcohol, marijuana or painkilling medications helpful. For example, many users report that SSRI and SNRI antidepressants often have both a slight stimulant effect and a slight numbing effect on their minds, and for some people these effects can help them manage distressing emotions and function in their daily lives. On the other hand, tricyclic antidepressants such as mirtazapine are much more likely to cause side effects of sedation, and so these drugs are more commonly prescribed for people having sleep problems alongside their feelings of anxiety or depression. In other words, some of the most commonly recognized side effects of certain antidepressants are for many people the primary means by which these drugs “work”.

Are antidepressants effective? – But first, what does “effective” mean?

We often hear that certain psychiatric drugs are effective. But it’s rarely explained what exactly “effective” means. Does effective mean that the drug makes everyone feel completely better? Or if some people feel better when taking the drug, in what ways do they typically feel better, by how much, and for how long a time? And do some people feel worse in certain ways because of the drug?

Unless you ask probing questions, or carefully and critically analyze scientific studies yourself, it’s difficult to know exactly what certain people mean when they state that a particular psychiatric drug is effective. Often, different people can even look at the same scientific evidence and reach opposite conclusions about whether a psychiatric drug demonstrated true effectiveness or not. (For more information, please read ICI’s “How Outcomes are Measured in Psychiatric Research” and “How Psychiatric Drugs are Researched and Marketed”.) Yet when deciding if a drug is right for you or for someone you care about, it is very important to have a strong understanding of in what ways the drug is apparently effective and to what degree it is apparently effective, so that you can reasonably weigh the potential benefits of the drug against its potential adverse effects.

As we described in our introductory section, one helpful way to resolve these challenges and learn about a psychiatric drug’s effectiveness is to examine the actual medical evidence that resulted in the FDA approving the drug to legally be described by the pharmaceutical manufacturer as “effective” for the drug’s intended use. This evidence comes from the clinical trials that a pharmaceutical company presented to the FDA in order to try to establish their drug’s effectiveness. Though these trials were sponsored and selected by the drug companies and so tended to be biased in favor of the drugs, they are still extremely instructive. So in this article, we provide some representative examples of how drug companies tried to prove to the FDA that their drugs were effective – and we examine what “effective” actually meant in that context.

How effective are antidepressants and in what ways are they effective in helping people diagnosed with Major Depressive Disorder?

Focusing on SSRIs and SNRIs as representative examples, the evidence presented by drug companies to the FDA suggests that antidepressants are effective for a few weeks to a couple of months at slightly reducing the frequency and intensity of some of the experiences linked to a diagnosis of Major Depressive Disorder.

For example, in 2002 the journal Prevention & Treatment published an analysis of 47 of the randomized, placebo-controlled clinical trials for antidepressants that were submitted to the FDA between 1987 and 1999 to gain approvals for 6 of today’s most commonly prescribed antidepressants. None of the trials were longer than 8 weeks in duration. In these trials, people’s depressed feelings were rated using a questionnaire called the Hamilton Rating Scale for Depression (HAMD or HRSD). (For more information, read ICI’s “How Outcomes are Measured in Psychiatric Research”.) Clinicians gave patients scores from 0 to 2 or 0 to 4 on issues like how much insomnia they seemed to be experiencing, how interested they seemed to be in their jobs, and whether they complained a lot. After 8 weeks, on 50-point or 62-point versions of the HAMD, people taking antidepressants typically scored only about 2 points lower (or 2 points “less depressed”) than people taking placebo pills.

And there were a number of reasons why this level of effectiveness of the antidepressants was likely even lower than it appeared to be:

  • The selection of trial participants was strongly biased in favor of the drugs: In the first 1-2 weeks people who were not responding well to the antidepressants were usually removed from the trials and not counted, while people who were responding well on placebo pills were removed and not counted.
  • The people taking the drugs always experienced many more adverse effects such as respiratory disorders, loss of strength, infections, constipation, nausea, somnolence, sweating and tremors. However, these adverse effects were not relevant to the measuring of the drugs’ effectiveness at reducing the frequency or intensity of the specific experiences linked to a diagnosis of depression.
  • There was evidence that the “blinding” may have been broken in many of the trials, since the antidepressant drugs produced such noticeable adverse effects. This created the possibility, since the clinicians were usually being paid by drug companies, that the scoring was biased in favor of the drug. Meanwhile, the patients taking placebo pills may no longer have received a true placebo effect, because they would have felt more certain that their pills were not actually drugs.
  • Though the 2-point difference in scores between the drug and placebo groups had statistical significance, there was no evidence that it had clinical significance, or meaningful significance for people’s actual experiences.

Nevertheless, based on these clinical trials, the FDA allowed the pharmaceutical companies to publicly promote that these drugs are effective in treating people diagnosed with Major Depressive Disorder.

When trying to appropriately weigh the potential benefits of antidepressants against their potential harms, it’s important to consider the limited effectiveness of these drugs.


Related reading:

Kirsch I, Moore TJ, Scoboria A, Nicholls SS (2002) The emperor's new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prev Treat. 5. article 23.

Kirsch, I., Sapirstein, G. (1998). Listening to Prozac but hearing placebo: A meta analysis of antidepressant medication. Prevention & Treatment, 1, Article 0002a

Kirsch, Irving, Brett J. Deacon, Tania B. Huedo-Medina, Alan Scoboria, Thomas J. Moore, and Blair T. Johnson. “Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration.” PLOS Medicine 5, no. 2 (February 26, 2008): e45. doi:10.1371/journal.pmed.0050045.

How effective are antidepressants in helping people diagnosed with anxiety disorders?

According to the evidence presented to the FDA, antidepressants seem to be effective for a few weeks to a few months in slightly reducing the frequency and intensity of some of the experiences linked to anxiety disorders.

As a representative example, in 2001 the FDA approved the SSRI antidepressant paroxetine (Paxil) for treating people diagnosed with Generalized Anxiety Disorder. This decision was based on two randomized, placebo-controlled clinical trials that lasted just 8 weeks. The participants’ levels of anxiety were scored by clinicians using a questionnaire called the Hamilton Anxiety Rating Scale. (For more information, read ICI’s “How Outcomes are Measured in Psychiatric Research.)

The clinicians gave the patients scores from 0 to 4 points on questions like how tense they seemed, how anxious they seemed, whether they were having any physical symptoms of anxiety like tension headaches or sighing, and whether they seemed restless while being asked these test questions. The people taking Paxil on average scored between just 2.3 and 3 points lower (or “better”) out of 56 total points than people taking placebo pills. On a separate 7-point scale rating overall improvement, the people taking Paxil scored only 0.3 points more improved than the people taking placebo pills.

And the FDA medical review showed how this level of effectiveness of the drug was likely even lower than it appeared to be:

  • The selection of trial participants was strongly biased in favor of the drugs: Any people who had been previously identified as not responding well to SSRI antidepressants like Paxil were excluded from participating in the trial, and in the first week, the people who were doing the best on placebo pills were removed from the trial and not counted.
  • Compared to those taking the placebo pills, the people taking Paxil experienced many more times the rates of adverse effects like respiratory disorders, loss of strength, infections, constipation, nausea, somnolence, sweating and tremors. In addition, eight times as many people taking the drug complained of having decreased libidos and seventeen times as many of the men complained about how the drug affected their ejaculations. However, these adverse effects were not relevant to the measuring of Paxil’s effectiveness at reducing the frequency and intensity of some of the specific experiences linked to anxiety.
  • After being on the drug for 8 weeks, the trial participants were tapered off the drug over the course of 2-3 weeks. During this taper phase, the people who’d been taking the drug reported withdrawal symptoms such as headaches, dizziness, diarrhea and abnormal dreaming.
  • The people taking placebo pills steadily improved through the course of the entire trial.
  • A third clinical trial of the same kind as the other two trials was conducted at the same time, but in this third trial Paxil definitively failed to reduce people’s anxiety any more than placebo pills.

Nevertheless, based on these clinical trials, the FDA allowed the pharmaceutical company to publicly promote that Paxil is effective in treating people diagnosed with Generalized Anxiety Disorder.

These results are a fair representation of the general level of effectiveness of antidepressants for treating people diagnosed with anxiety disorders. For example, in 2015 JAMA Psychiatry published a meta-analysis of 57 trials of antidepressants that were submitted by drug companies to the FDA between 1994 and 2008 seeking approvals for treating people diagnosed with various anxiety disorders. These studies showed that antidepressants had generally similar, very limited levels of effectiveness – about the same limited overall effectiveness that was found in the clinical trials for treating people diagnosed with Major Depressive Disorder (see above).

When trying to appropriately weigh the potential benefits of antidepressants against their potential harms, it’s important to consider these limited effectiveness rates.


Related reading:

U.S. Food and Drug Administration. Drug Approval Package – Paxil (Paroxetine Hydrochloride) – Medical Review. (April 13, 2001)

Roest AM, de Jonge P, Williams CD, de Vries Y, Schoevers RA, Turner EH. Reporting Bias in Clinical Trials Investigating the Efficacy of Second-Generation Antidepressants in the Treatment of Anxiety Disorders: A Report of 2 Meta-analyses. JAMA Psychiatry. Published online March 25, 2015. doi:10.1001/jamapsychiatry.2015.15.

How effective are antidepressants for helping people diagnosed with Post-traumatic Stress Disorder (PTSD)?

Only two antidepressants have been approved by the FDA for treating people diagnosed with Post-traumatic Stress Disorder (PTSD) – paroxetine (Paxil) and (sertraline) Zoloft. According to the evidence provided to the FDA, these drugs seem to be effective for a few weeks to a few months at slightly reducing the frequency or intensity of some of the experiences that are commonly associated with a diagnosis of PTSD.

As a representative example, two clinical trials of 12 weeks in duration were submitted to the FDA to establish the effectiveness of Zoloft in helping people diagnosed with PTSD. In the trials, the clinicians used a questionnaire called the Clinician Administered PTSD Scale that asked participants about experiences they were having such as intrusive thoughts, efforts to avoid certain thoughts, distress in relation to reminders of memories, diminished interest in activities, difficulty sleeping, hypervigilance, and irritability or anger. The clinicians scored participants from 0 to 4 on the apparent frequency and intensity of each of these kinds of experiences. Out of 136 total points, the people taking Zoloft scored on average only about 8 points lower (or “better”) than the people taking placebo pills. On another scale where the participants rated themselves, out of 75 total points the participants taking Zoloft scored on average just about 4.5 points lower than the people taking placebo pills.

And the FDA medical review showed how this level of effectiveness of the drug was likely even lower than it appeared to be:

  • The selection of trial participants was strongly biased in favor of the drugs: Anyone who was identified as not being a good responder to Zoloft or other similar SSRI antidepressants was excluded from participating in the trial.
  • Overall, only the women achieved lower scores when taking Zoloft; the men taking Zoloft did not score any lower than the men taking placebo.
  • The trials included three times as many women as men, and significantly more of the men were placed in the placebo group. If the men had been appropriately distributed between both the plaebo and drug groups, or if there’d been closer to 50% of each gender in the trials, Zoloft would not have performed better than placebo.
  • There were no improvements that were actually directly related to dealing with disturbing memories. The only improvements occurred on issues related to general feelings – the FDA review indicated that this simply showed that the “mood” of the female participants had apparently been lifted slightly during the trials, not that their PTSD-specific symptoms had been alleviated.
  • The people taking Zoloft experienced much higher rates of adverse side effects such as dry mouth, fatigue, anorexia, decreased libido, and tremors, but this was not relevant to the measuring of the effectiveness of Zoloft at reducing the frequency or intensity of some of the specific experiences linked to a diagnosis of PTSD.
  • Two other, similar clinical trials were conducted by the drug company at the same time, and in those trials Zoloft definitively failed to help people more than placebo did.

Indeed, considering all of these factors, the lead FDA medical reviewer actually concluded that the scientific evidence recommended against approving Zoloft for treating people diagnosed with PTSD. Nevertheless, the FDA dismissed the recommendation of its own medical review (see page 41) and, on the basis of these clinical trials, the FDA approved Zoloft as effective for treating people diagnosed with PTSD.

The clinical trials for Paxil (paroxetine) showed generally similar results. Three 12-week trials were conducted by the drug company, and in one of them Paxil definitively failed to help people more than placebo, while in two of the trials people taking Paxil achieved slightly lower scores. The lead FDA medical reviewer noted that the improvements in the people taking Paxil were so slight, though, that all of the participants were still by definition “clinically ill”, and he pondered whether these tiny statistical improvements in scores were even “clinically relevant” or not. Nevertheless, Paxil was also approved as effective for treating people diagnosed with PTSD.

When trying to appropriately weigh the potential benefits of antidepressants against their potential harms, it’s important to consider these limited effectiveness rates.


Related reading:

U.S. Food and Drug Administration. Drug Approval Package – Zoloft (Sertraline Hydrochloride) – Medical Review and Statistical Review. (September 12, 1999)

U.S. Food and Drug Administration. Drug Approval Package – Zoloft (Sertraline Hydrochloride) – Medical Review Part 1. (p. 41). (1999)

U.S. Food and Drug Administration. Drug Approval Package – Paxil (Paroxetine Hydrochloride) – Medical Review. (December 27, 2001)

Are antidepressants effective for children?

Several antidepressants have been approved by the FDA for children, but only for very specific indications (check the drug label). Generally, the effectiveness of antidepressants in children has been shown to be even less than it is in adults (see above). Meanwhile, the adverse effect risks tend to be higher than in adults, such as the risks for increased suicidal feelings and thoughts (see below).

Of additional concern, numerous studies and reviews have identified that the findings of only a small percentage of the antidepressant trials done on children have ever been made public, and that even the relatively few published trials tend to show the drugs have no effectiveness outside of the common placebo effect, while there are significant risks of harms from the drugs.


Related reading:

University of British Columbia Therapeutics Initiative. Antidepressant medications in children and adolescents. Therapeutics Letter 2004;52.

How effective are antidepressants for long-term use?

Some antidepressants have been approved by the FDA for longer-term management or maintenance treatment for people diagnosed with various mental disorders. However, most of these studies do not provide evidence of long-term effectiveness in the way that most of us would normally understand it. While many people take antidepressants for years or even decades, most long-term studies of antidepressant effectiveness that have been submitted to the FDA are less than two years in length. And the vast majority of these are relapse studies – that is, they don’t set out to prove that people continue to become better on the drugs, rather they try to prove that when people abruptly stop taking the drugs they tend to become worse. This is an important difference.

Typically in these kinds of studies submitted to the FDA, pharmaceutical company-paid researchers identify people who have been taking the company’s drug for a period of time already and then select only those people who have been responding the best to that drug. These ideal responders are then divided into two groups – one group of people who will continue to receive the drug, and another group of people who will be abruptly withdrawn from the drug and put on placebo pills instead. Though it is known that antidepressants are dependence-forming and require careful, slow tapering, in long-term antidepressant trials people in the placebo groups are generally taken off the drugs extremely rapidly and many likely suffer severe withdrawal symptoms. Yet none of the researchers in these trials ever attempt to differentiate between which experiences are emerging symptoms of mental disorders and which are emerging psychological drug withdrawal effects – all of the problematic experiences that arise for people, no matter what they are, get labeled as “recurrences of underlying mental disorders”.

This is a serious problem that potentially distorts the findings of nearly all longer-term antidepressant trials. Indeed, when reviewing these maintenance trials, some FDA medical reviewers have expressed concerns about this issue and have identified the need for more studies of antidepressant withdrawal and safe tapering.

As a representative example of this phenomenon, a study submitted to the FDA to establish the long-term effectiveness of the antidepressant Effexor XR in treating people diagnosed with Major Depressive Disorder was just 18 months long. First, people were given Effexor XR daily for 6 months. Then, the researchers selected only those people who were responding the best to the drug to continue in the next part of the trial. At this point, the ideal drug responders were divided into two groups – those that would simply continue taking the drug, and those that would be secretly taken off their drug within 1-2 weeks. All of these people were then monitored for relapses. “Relapses” were determined to have occurred when a clinician determined that a patient had transitioned into becoming “moderately ill”, “markedly ill” or worse, as opposed to remaining “mildly ill”, “borderline ill” or better.

Over the next year, 55% of the people taking placebo relapsed once, while about 23% of the people taking the drug relapsed once. However, after 6 months of daily use of the drug, some of the people put into the placebo group would certainly have started suffering drug withdrawal symptoms when they were so rapidly withdrawn. These possible drug discontinuation symptoms, according to Effexor XR’s own drug label, would have included mild-to-severe anxiety, insomnia, lethargy, emotional problems, confusion, somnolence, not eating, and a host of other symptoms that are themselves commonly viewed by clinicians as a worsening or relapse of Major Depressive Disorder. This potential complicating factor in the study’s findings was not addressed by the researchers.

Also of note is the fact that the vast majority of these relapses in the placebo group occurred within the first three months, shortly after the participants were abruptly withdrawn from their drug. After those first few months, the relapse rates in the drug and placebo groups were actually the same. And by the final few months of the trial, a year later, no one in the placebo group was relapsing anymore.


Related reading:

U.S. Food and Drug Administration. Drug Approval Package – Zoloft (Sertraline Hydrochloride) – Medical Review and Statistical Review. (August 17, 2001)

U.S. Food and Drug Administration. Drug Approval Package – Effexor XR – Medical Review and Statistical Review. (May 2, 2001)

If antidepressants are not very effective, why do I/do some people seem to become much better when taking them?

If you read all of ICI’s mini-booklets on the major psychiatric drug classes you will notice that, based on the clinical trial information that was provided to the FDA, most psychiatric drugs seem to have at best very modest, short-term effectiveness in helping people diagnosed with mental disorders. These findings generally match the findings in the broader scientific literature as well. Yet some people report that they benefit immensely from taking certain psychiatric drugs. What is going on?

Many psychiatric drug trials do show that a percentage of people respond much more positively than most other people to certain psychiatric drugs. However, the studies generally cannot shed light on why that’s happening. Are these random, “lucky” occurrences? Is there a particular subgroup of people who respond better to certain psychiatric drugs due to unknown genetic, biochemical or lifestyle differences? Do a person’s responses tend to be greater or smaller depending on what is actually causing the person’s problems?

One important factor has been extensively studied: Psychiatric drug trials tend to have the highest placebo response rates in all of medicine. Most psychiatric drug trials show the majority of participants scoring substantially better on improvement tests whether they are taking a drug or placebo – apparently, simply hoping or believing that they are taking a potentially helpful psychiatric drug seems to be very helpful for many people. Indeed, in most trials this placebo effect accounts for a much larger portion of people’s apparent improvements than the drugs themselves. So while we can determine scientifically that the overall positive effects of a particular psychiatric drug are relatively modest, some people will experience the effect of the drug plus a very substantial placebo effect, which can make the drug seem to be much more effective than it otherwise might to those people personally.

There can also be, for example, “social placebo” effects, where having the encouragement and support of mental health professionals, family, and other people around you when you take a psychiatric drug can change both their and your feelings and behaviors in ways that can contribute significantly to the positive overall impacts of a drug. In addition, after experiencing some initial benefits from a drug, over time some people can have a tendency to attribute further positive developments in their moods and experiences to the drug while attributing negative developments to re-emergence of their own underlying problems.

Alternatively – and some experts argue most importantly – some people might simply more strongly like or have positive therapeutic responses to the sedating, numbing or stimulating effects of certain prescribed psychiatric drugs on their feelings, experiences or behaviors, in similar ways to how some people respond positively to the effects of coffee, cigarettes, painkilling medication, alcohol, marijuana or other drugs.

If antidepressants are not very effective, why do I/do some people seem to become much worse when stopping them?

Many people find that, when they stop taking psychiatric drugs after long periods of regular use, they rapidly start to feel worse. They may then believe (or they may have been told by their prescriber or others) that this is because the underlying problem that the drug was treating has re-emerged. This could be the case; however, there is actually a more likely explanation.

All psychiatric drugs are, to greater or lesser degrees, dependence-forming – today, the majority of drug labels for all classes of psychiatric medications include indications of this fact. Benzodiazepines, stimulants, and Z-drugs are specifically classified as Controlled Substances in the United States due to their potential for causing dependence and addiction. And the drug labels for most antidepressants and anticonvulsant “mood stabilizer” drugs, along with many antipsychotics, include specific cautions about “drug discontinuation syndromes” (withdrawal symptoms) that have been observed.

Essentially, “dependence-forming” means that, over time, the human body adjusts to the presence of these drugs in biochemical and structural ways. When stopping the drugs suddenly, many people will experience very uncomfortable or even dangerous physical and mental withdrawal symptoms, as the body is forced to rapidly re-adjust to the absence of the drugs.

Among many other possible withdrawal symptoms, abrupt discontinuation of psychiatric drugs commonly produces unusually extreme and intense manifestations of some of the feelings, experiences or behaviors that the drugs were helping to suppress. For example, stopping a sedating drug is likely to cause withdrawal symptoms such as abnormally intense anxiety and agitation. Stopping a numbing drug is likely to cause withdrawal symptoms such as hypersensitivity and moodiness. Stopping a stimulant drug is likely to lead to feelings of unusually intense depression. Moreover, some withdrawal symptoms can continue for weeks, months, or even years until the body and brain have had enough time to fully re-adjust to the absence of the drug. (For more information, see The Withdrawal Project’s overview essay, “Psychiatric Drug Tolerance, Dependence and Withdrawal”.)

How safe or dangerous are antidepressants? Do I really need to read about and concern myself with all of those apparently minor or rare adverse effects?

It’s often claimed that psychiatric drugs are safe. But what does “safe” actually mean? Different people can mean different things when they say that a drug is generally safe.

The FDA requires pharmaceutical companies to conduct some basic studies into the safety of their drugs. The findings from these studies are then included in the official FDA-approved drug labels under the assumption that patients and prescribers will then together review and weigh a drug’s potential risks and benefits. All prescribing physicians, psychiatrists and pharmacists are ethically and legally required to ensure that patients are informed about the potential harms of any drug that is being prescribed to them. In practice, though, this rarely occurs with respect to any drugs let alone psychiatric drugs, and patients often receive information which is incomplete or inaccurate. 

Prescribers themselves are not always fully informed. The lists of potential adverse effects for most psychiatric drugs are lengthy, and many prescribers are too busy to either learn about them all or, if they do learn them, convey them all to patients. Some prescribers don’t want to dissuade or frighten people from taking psychiatric drugs that they are recommending. Even the more responsible prescribers often just direct patients to read unregulated information or brief highlights of the drug labels that may accompany packages of prescription drugs. Relatively few of us ever read even these inserts, though, and instead we simply trust general reassurances from prescribers. This attitude is usually founded on a basic, deep trust of the medical profession, drug regulators, and scientific research. To learn more about why this trust should be balanced with healthy skepticism, please read ICI’s “How Psychiatric Drugs are Researched and Marketed”.

As we discussed in our introduction, even though the risk and safety information included in the drug labels tends to be biased in favor of the drugs, these labels can still be very informative. That said, it’s easy to feel like it’s not worth the effort to read about all of the adverse effects identified in these lengthy drug labels, because many of them can seem relatively trivial, while many of the more serious side effects are identified as being rare. However, there are other important factors to take into consideration:

  • The real adverse effect rates are unknown and often higher. Most of the adverse effects that are listed in the FDA-approved drug labels are the ones that appeared in relatively short clinical trials involving small numbers of people – so the actual adverse effects in typical users are unknown, and reasonably likely to be (and are often later found to be) much larger in number and varied in type. Indeed, sometimes the drug labels include reports of many more adverse effects in a section called “Post-marketing Experience” – these are lists of adverse effects that started being identified and voluntarily reported to the FDA after many more people in the general population began regularly using the drugs. Because these reports are voluntary, though, the absence of such reports cannot be taken as evidence of a drug’s safety.
  • "Infrequent" doesn’t always mean unlikely. It’s true that any particular, individual user is relatively unlikely to experience any one particular, infrequent adverse effect. However, taken all together, in most cases it’s very likely that most users will experience at least some of the listed adverse effects.
  • "Rare" can add up to a lot of people. In the drug labels, some potentially very serious adverse effects may be described as “rare”. This refers to the fact that small numbers of people will experience a particular adverse effect relative to the overall number of people taking the drug. However, it’s important to remember that, with millions of Americans taking certain psychiatric drugs, “rare” can easily mean that thousands or ten of thousands of Americans will be experiencing that very serious adverse effect.
  • Minor adverse effects may be warning signs. Apparently minor adverse effects can sometimes be early warning signs for more serious, rarer adverse effects; therefore, knowing the minor adverse effects could help prevent more serious harms or even, sometimes, save your life. 
  • Adverse effects reveal a lot about how a drug works. Understanding the full range of possible adverse effects helps you better understand the ways in which a drug is acting on your body and brain.
  • Your choice is better informed. Understanding the adverse effects helps you make a more informed choice about whether, for you, the relative effectiveness of a drug truly outweighs the potential harms.

Deciding to take a psychiatric drug or encouraging a friend or loved one to take a psychiatric drug, especially when it could potentially be for a long time, is a significant choice that could change the course of your or someone else’s life. The only way to make a truly, meaningfully informed choice is to try to ensure that you get the best information and advice that you can to help you think through the decision. If you or someone close to you is taking or considering taking any psychiatric drug, we encourage you to make the time to read the entire drug label. In this article, we have reviewed only a small sampling of the adverse effects identified in these labels, so below we also include links to several places where the U.S. FDA-approved drug labels can be viewed freely in full. However, in light of the limitations of this information, it’s even better to supplement it by examining the FDA’s “drug approval packages” (which include internal medical reviews of a drug), doing wider research, and consulting with well-informed, supportive practitioners.

At the same time, for anyone taking any psychiatric drug, the complexity of all of this information is an important reminder of the vital importance of always trying to listen closely to the wisdom in what your own body is telling you.


Related reading:

Instructions and links for obtaining and understanding drug labels can be found in “The Withdrawal Project's Guide to the FDA-approved Drug Labels”.

U.S. Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products.

U.S. Food and Drug Administration. Drugs@FDA Instructions: Health Information. (A quick guide to searching the FDA’s drug information system.)

U.S. National Library of Medicine. DailyMed

What are the immediate and most common adverse effects of antidepressants?

There are so many different types of antidepressants, it is impossible to briefly summarize all of their many and varied adverse effects. Generally, all antidepressants disrupt the functioning of a number of key neurotransmitters that play important roles throughout the main communications systems of the brain and body – this is why they can have such a wide range of adverse effects even at their recommended dose levels, and even in very short-term use.

That said, many of the adverse effects are dose-dependent – at the higher range of commonly prescribed doses, the adverse effects rates tend to be higher. For example, in short-term clinical trials it’s common to see these types of adverse effects from antidepressants:

  • Up to 15% of people develop tremors.
  • Up to 20% of people develop somnolence or sleepiness, while conversely rates of insomnia also increase.
  • Up to 15% of people experience loss of muscle strength and fatigue.
  • Abnormal and bizarre sensations in the body such as numbness, tingling, pricking or burning occur in up to 6% of people.
  • Blurred vision develops in up to 8% of people.
  • Compared to people taking placebo, dizziness rates quadruple, nausea rates quadruple,  abnormal sweating quintuples, and both diarrhea and constipation rates double.
  • The risks of both anorexia and weight gain increase.
  • The risks of bone fractures doubles.
  • Abnormal bleeding and bruising increases.

Below, we discuss in detail some of the other common adverse effects of antidepressants, such as impacts on sexual function, suicidal feelings, and emotional stability. It is important to keep in mind that the focus throughout is on the more commonly used, newer drugs such as SSRI and SNRI antidepressants; the older drugs such as tricyclic antidepressants generally have much worse adverse effect profiles. Aside from the FDA-approved drug labels and other studies cited, we draw frequently from a 2016 review of antidepressant adverse effects published in Psychotherapy and Psychosomatics.


Related reading:

Carvalho, A. F., M. S. Sharma, A. R. Brunoni, E. Vieta, and G. A. Fava. “The Safety, Tolerability and Risks Associated with the Use of Newer Generation Antidepressant Drugs: A Critical Review of the Literature.” Psychotherapy and Psychosomatics 85, no. 5 (August 11, 2016): 270–88. doi:10.1159/000447034.

How much of a negative impact do antidepressants have on libido, sexual function and orgasms?

All of the antidepressants can have negative impacts on sexual function. These effects have been most extensively studied with respect to the SSRI and SNRI antidepressants – the most commonly used antidepressants. According to their drug labels, in short-term trials, these drugs caused up to 9% of women to experience decreased libido, and up to 9% to experience difficulty or inability in reaching orgasm. For men, the effects were even more pronounced. Disturbances and delays in ejaculation were reported by up to 28% of men taking antidepressants, and up to 10% of men reported becoming impotent. These high rates typically compared to rates of 0-3% in the placebo groups. Some studies have found the rates of adverse sexual effects as high as 50-70% among antidepressant users. The drug labels add that these adverse effects likely underestimate the actual rates of sexual dysfunction caused by antidepressant drugs, because researchers and medical doctors are “reluctant to discuss” these issues with patients.

Though the research into the phenomenon is preliminary, anecdotal reports and studies are emerging to suggest that for some people normal sexual function does not return even after they stop taking antidepressants.


Related reading:

Ben-Sheetrit, Joseph, Dov Aizenberg, Antonei B. Csoka, Abraham Weizman, and Haggai Hermesh. “Post-SSRI Sexual Dysfunction: Clinical Characterization and Preliminary Assessment of Contributory Factors and Dose-Response Relationship.” Journal of Clinical Psychopharmacology 35, no. 3 (June 2015): 273–78. doi:10.1097/JCP.0000000000000300.

Are antidepressants safe during pregnancy?

There are so many different types of antidepressants, it is impossible to summarize the risks they present to pregnant mothers, fetuses and infants. According to their drug labels, antidepressants have generally not been sufficiently tested in pregnant or lactating women to provide a definitive sense of how risky they are. Nevertheless, antidepressants interfere with the functioning of body and brain neurotransmitters, which are fundamental to fetal development, so it seems likely that the risks of taking these drugs during pregnancy would be significant.

SSRI and SNRI antidepressants are known to pose significant risks to fetuses, including increased risks of malformations and defects, particularly in the cardiovascular system. According to their drug labels, infants born to mothers taking these common antidepressants have also been found to have a higher likelihood of suffering a variety of serious problems such as respiratory distress and breathing disruption, discoloration of the skin caused by inadequate oxygen intake, seizures, inability to properly regulate temperature, vomiting, blood sugar regulation problems, muscle and motor dysfunctions of various kinds including “floppy baby syndrome”, irritability, and constant crying. The drug labels indicate that it is unclear whether these impacts are “a direct toxic effect” of the drugs, or if the infants are suffering from drug withdrawal symptoms.

Infants exposed to certain antidepressants in pregnancy also seem to have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). This involves the fetus not receiving sufficient oxygen, and can lead to a host of other serious developmental problems in the brain and body and even fetal death.

The general research literature has raised more concerns – further reading is included below.


Related reading:

Adam Urato, an Obstetrics and Gynecology medical doctor, has compiled a list of scientific references about antidepressants and pregnancy for a Mad in America Continuing Medical Education course: “Antidepressants in Pregnancy: Risks to the Fetus and Long-term Health of the Child”. (October 2, 2016)

Boukhris, Takoua, Odile Sheehy, Laurent Mottron, and Anick Bérard. “Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children.” JAMA Pediatrics 170, no. 2 (February 2016): 117–24. doi:10.1001/jamapediatrics.2015.3356.

Pedersen, Lars Henning, Tine Brink Henriksen, and Jørn Olsen. “Fetal Exposure to Antidepressants and Normal Milestone Development at 6 and 19 Months of Age.” Pediatrics 125, no. 3 (March 2010): e600-608. doi:10.1542/peds.2008-3655.

Simpson, Kimberly L., Kristin J. Weaver, Etienne de Villers-Sidani, Jordan Y.-F. Lu, Zhengwei Cai, Yi Pang, Federico Rodriguez-Porcel, Ian A. Paul, Michael Merzenich, and Rick C. S. Lin. “Perinatal Antidepressant Exposure Alters Cortical Network Function in Rodents.” Proceedings of the National Academy of Sciences of the United States of America 108, no. 45 (November 8, 2011): 18465–70. doi:10.1073/pnas.1109353108.



Is it true that antidepressants can increase suicidal feelings?

All antidepressant drugs come with strong “black box” warnings from the FDA that these drugs significantly increase the risk of suicidal thoughts and feelings in everyone under the age of 24. The drug labels do not include a specific risk ratio, but some meta-analyses of placebo-controlled studies have found that antidepressants increase the risk of experiencing suicidal feelings and thoughts by 2-3 times.

The FDA warnings also note that a diagnosis of depression itself has been linked at times to a higher risk of having suicidal feelings. This is important to consider; however, sometimes this statement confuses people because it seems to suggest that the scientific studies may simply be showing that there are higher rates of suicidal feelings among people diagnosed with depression. This is an incorrect interpretation. What the studies show is that, regardless of whether people are already feeling depressed or suicidal or not, antidepressants more than double the rates of suicidal feelings and thoughts in everyone under the age of 24.

It is unclear if or why these effects would only occur in people up to the age of 24. The manner of recording suicidal thoughts, feelings and attempts in antidepressant clinical trials has been the subject of controversy, and some analyses suggest that the data show that antidepressants increase suicide rates among older adults as well.


Related reading:

Sharma, Tarang, Louise Schow Guski, Nanna Freund, and Peter C. Gøtzsche. “Suicidality and Aggression during Antidepressant Treatment: Systematic Review and Meta-Analyses Based on Clinical Study Reports.” BMJ 352 (January 27, 2016): i65. doi:10.1136/bmj.i65.

Healy, David, and Graham Aldred. “Antidepressant Drug Use & the Risk of Suicide.” International Review of Psychiatry (Abingdon, England) 17, no. 3 (June 2005): 163–72. doi:10.1080/09540260500071624.


Is it true that antidepressants can increase aggressiveness, hostility, homicidal ideation and violence?

The drug labels for all antidepressants warn that these drugs seem to be able to cause “unusual changes in behavior” that can present serious risks to the person taking the drug or to others, especially during the first few months of taking an antidepressant or during increases or decreases of doses. According to the drug labels, these changes in behavior include increases in “anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania.”

Acts of violence have been found to double in frequency in people who take antidepressants, even when those people are not diagnosed with any mental disorders. Other studies have found that antidepressant drugs are linked to acts of serious violence much more often than other psychiatric drugs.


Related reading:

Bielefeldt, Andreas Ø, Pia B. Danborg, and Peter C. Gøtzsche. “Precursors to Suicidality and Violence on Antidepressants: Systematic Review of Trials in Adult Healthy Volunteers.” Journal of the Royal Society of Medicine 109, no. 10 (October 1, 2016): 381–92. doi:10.1177/0141076816666805.

Moore, Thomas J., Joseph Glenmullen, and Curt D. Furberg. “Prescription Drugs Associated with Reports of Violence Towards Others.” PLOS ONE 5, no. 12 (December 15, 2010): e15337. doi:10.1371/journal.pone.0015337.


If I take them for a long time, can antidepressants start to make me more depressed?

Studies indicate that the incidence of what’s sometimes called “treatment-resistant depression” has been increasing dramatically. These are situations in which people diagnosed with Major Depressive Disorder seem to respond well to antidepressants for a short period of time, but over a longer period they become more frequently, chronically and intensely depressed even though they continue to take the drugs. Some estimates suggest that as many as 30-50% of people who have taken antidepressants for very long periods of time now fall into this category. It is a matter of speculation as to what exactly might be causing it.


Related reading:

Rif S. El-Mallakh, Yonglin Gao, R. Jeannie Roberts. “Tardive dysphoria: The role of long term antidepressant use in-inducing chronic depression.” Medical Hypotheses. Volume 76, Issue 6, June 2011. Pages 769-773. (Also available here.)

Can antidepressants cause difficulty concentrating, confusion and memory impairment?

Antidepressants are psychoactive chemicals, and so not surprisingly they can cause some people to experience a variety of problems with thinking and memory like most psychoactive chemicals can do.

SSRIs and SNRIs in particular, though, create a higher risk of developing a physical condition called hyponatremia, which involves serum sodium levels in the body dropping below healthy levels. According to their drug labels, this can lead to headaches, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness. As the condition worsens, it can lead to hallucinations, seizures, coma, respiratory arrest, and even death.

Unusually low sodium serum levels have been found in 9-40% of antidepressant users. Though the overall risk of extremely low, life-threatening serum levels occurring seems to be relatively small overall and dependent on other physical and lifestyle factors, a 2016 study found that nine newer antidepressants created a five-times-higher risk of being hospitalized due to hyponatremia.


Related reading:

Gandhi, Sonja, Salimah Z. Shariff, Ahmed Al-Jaishi, Jeffrey P. Reiss, Muhammad M. Mamdani, Daniel G. Hackam, Lihua Li, Eric McArthur, Matthew A. Weir, and Amit X. Garg. “Second-Generation Antidepressants and Hyponatremia Risk: A Population-Based Cohort Study of Older Adults.” American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation, October 20, 2016. doi:10.1053/j.ajkd.2016.08.020.

Can antidepressants cause mania, or lead to a diagnosis of Bipolar Disorder?

All antidepressants come with FDA warnings that the drugs can cause hypomania and mania. This is likely related to the stimulating effect that these drugs cause in many people. In some short-term trials of antidepressants, 1 in every 100 people was thrown into some kind of manic reaction by the drugs, such as unusually racing thoughts, intense sensory experiences, risky, impulsive behaviors, insomnia, and aggressiveness. Other, longer studies have suggested much higher rates of these kinds of behavior changes, especially in children and youth.

In this manner, antidepressants can change the experiences or behaviors of some people in ways that may lead those people to get diagnosed with manic depression or Bipolar Disorder.


Related reading:

Martin, Andrés, Christopher Young, James F. Leckman, Chengeto Mukonoweshuro, Robert Rosenheck, and Douglas Leslie. “Age Effects on Antidepressant-Induced Manic Conversion.” Archives of Pediatrics & Adolescent Medicine 158, no. 8 (August 1, 2004): 773–80. doi:10.1001/archpedi.158.8.773.

Can antidepressants cause hallucinations, seizures or even death? What is “serotonin syndrome”?

The drug labels for most antidepressants warn about a condition called “serotonin syndrome”. This occurs when the drug hyperactivates the serotonin neurotransmitters in the body and brain. It is extremely rare for a severe version of this syndrome to occur when taking only a single antidepressant on its own. The likelihood increases dramatically, though, when a person is simultaneously taking other drugs that also affect the serotonin system, such as cocaine, some dietary supplements, certain painkilling drugs, or other antidepressants.

The syndrome can lead to agitation, hallucinations, delirium, instability in blood pressure, temperature, and heart rate, neuromuscular symptoms such as tremors, rigidity, overactive reflexes and loss of coordination, and/or gastrointestinal symptoms such as nausea, vomiting, and diarrhea. It can also lead to coma and death. Usually, the most potentially dangerous known drug interactions are identified in the Full Prescribing Information section of the drug label.


Related reading:

Volpi-Abadie, Jacqueline, Adam M. Kaye, and Alan David Kaye. “Serotonin Syndrome.” The Ochsner Journal 13, no. 4 (2013): 533–40.


Some of the side effects from psychiatric drugs seem to diminish over time – isn’t that a good thing?

When you complain about adverse effects after starting a psychiatric drug, it is common for physicians and psychiatrists to advise you to continue to take the drug anyway because some adverse effects will likely stop. Even popular medical websites like WebMD do this, advising that some of the adverse effects “may go away after you take the medicine for a while” because “your body can adjust” to the presence of the drugs.

This is certainly possible. What is not often explained, though, is that this body “adjustment” indicates growing drug tolerance. Your body is compensating for the presence of a foreign chemical and is developing ways to diminish some of the chemical’s impacts. So while you may begin experiencing fewer adverse effects or less intense adverse effects as your body compensates and adapts to the presence of the drug, it’s possible that you’ll begin experiencing decreased beneficial effects as well. And other adverse effects will often be continuing, if unnoticed.

Further, this increasing tolerance also indicates that your body is starting to develop physical dependence on the drug, which could bring the risk of uncomfortable, painful or even dangerous withdrawal symptoms if you try to stop the drug suddenly. Prescribers should warn patients more often about the risks of developing dependency on and tolerance to psychiatric drugs, but they often do not.

Can antidepressants cause dependence to develop even at normal dosages prescribed by my doctor or psychiatrist?

Antidepressants are not considered to be addictive drugs. They do not induce “cravings” after a period of regular use. However, antidepressants are known to be dependence-forming at any prescribed dosage level. This means that over time the body and brain adjust and adapt to the presence of the drug, and people can experience a wide variety of difficult or even dangerous withdrawal symptoms when they abruptly stop taking the drug. This is sometimes called “discontinuation syndrome”. The drug labels for most antidepressants warn that the drugs should not be discontinued abruptly.

It is not fully understood how antidepressants affect the body and brain, and so it is also not understood exactly how abrupt discontinuation of these drugs can produce difficult or dangerous withdrawal symptoms after a period of regular use. However, it is known that antidepressants typically disrupt and alter the functioning of important neurotransmitters such as serotonin and norepinephrine. (Neurotransmitters are the key chemical messengers in the brain and body’s internal communications and functional systems.) For example, most antidepressants seem to, at least early on, increase the amount of the neurotransmitter serotonin that is re-circulating in the brain. Over time, human and animal studies suggest that the brain may then compensate for this “overload” of serotonin by biologically reducing its sensitivity to serotonin and/or by reducing its own natural production of serotonin. Consequently, if a person then suddenly stops taking the drug, the person may experience a sudden, dramatic drop in serotonin levels that is utterly unlike anything that would ever have naturally occurred before the person started taking the drug.

In other words, we could think of an antidepressant as a sort of “gas pedal” that creates higher serotonin levels and, over a period of time, the body compensates by pressing more and more on its own internal serotonin “brake”. So if the drug-induced serotonin gas pedal suddenly stops pressing, while the body’s own serotonin brake is still pressing hard, what happens? What are the psychological and physical effects of this sudden, dramatic drop in serotonin levels on a person, especially when serotonin is involved in many different functions of the brain and body from appetite, temperature regulation, wakefulness, sleep and attention to sensory perceptions, emotions and moods? And serotonin is only one of the neurotransmitters that antidepressant drugs significantly affect. The drugs are also known to affect, for example, norepinephrine, glutamate and dopamine, which are centrally involved in many other basic functions of the brain and body. How are sudden changes to the activities of a host of major neurotransmitters experienced by a person, when those neurotransmitters are involved in virtually every physical, psychological, emotional and cognitive process in the brain and body?

According to their drug labels, after just 8-12 weeks of taking many common antidepressants, possible symptoms of abrupt discontinuation include dizziness, nausea, headache, tinnitus, irritability, insomnia, diarrhea, anxiety, lethargy, fatigue, abnormal dreams, and excessive sweating. More serious symptoms of antidepressant withdrawal include dysphoric mood, agitation, bizarre sensory disturbances, anxiety, confusion, extreme emotional shifts, hypomania, and seizures. These symptoms tend to be more common, frequent and intense after longer periods of regular use of antidepressant drugs.


If I want to stop taking antidepressants, what should I know?

Although antidepressant “discontinuation syndrome” is recognized and discussed in the drug labels for antidepressants, there are virtually no formal scientific studies into the safest methods or time frames for tapering.

Stopping any psychiatric drug can be risky or even dangerous. In particular, many official drug labels, formal scientific studies, and a growing evidence base of anecdotal reports from physicians and patients alike suggest that coming off psychiatric drugs abruptly or too rapidly for the central nervous system to manage tends to be especially risky and in some circumstances can even produce severe seizures or other life-threatening withdrawal reactions. Therefore, aside from situations where a medical emergency may deem rapid withdrawal to be necessary, tapering off a psychiatric drug is a major decision that is very personal and should involve forethought and careful planning. All of the possible benefits, risks and consequences of tapering should be carefully weighed in light of each individual’s life circumstances, physical health, resources, supports, and other factors.

If you or someone close to you is considering tapering, you may find it helpful to visit The Withdrawal Project, where ICI has been gathering the anecdotal reports and accumulated insights from laypeople who have experienced psychiatric drug withdrawal. There you can find discussions about common methods of tapering, what “slow” and “responsible” tapering looks like, how to prepare for tapering, and how to develop a plan of action for withdrawal that ideally involves the collaborative support of a well-informed prescriber, pharmacist, family and friends. At TWP Connect, people considering coming off psychiatric drugs can also connect with others who have experienced psychiatric drug withdrawal, are in withdrawal, or are considering withdrawal. (If you’re simply generally interested in connecting with others who are learning more and thinking critically about all things “mental health”, please consider joining ICI Connect.)