"Antipsychotics"

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.

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.

Antipsychotics are a class of psychotropic drugs that are sometimes also called neuroleptics or tranquilizers. The first neuroleptics were discovered in the middle of the 20th century and were initially used, for example, as antihistamines, painkillers and anesthetics. Eventually, psychiatrists and physicians began to give the drugs to people diagnosed with schizophrenia and psychosis, and the name “antipsychotic” became common. Today, however, some psychiatrists and physicians also prescribe these drugs to people diagnosed with Bipolar Disorder, ADHD, Major Depressive Disorder, Generalized Anxiety Disorder and dementia, for behavior control, and as sleep aids. Some of these indications are approved by the U.S. Food and Drug Administration (FDA) while many are "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”.)

The first antipsychotics developed are now commonly described as “typical” antipsychotics, while most of the newer ones are called “atypical”. Common generic names for older, first generation, typical antipsychotics include haloperidol and chlorpromazine (e.g. U.S. brand names Haldol and Thorazine). Second generation, atypical antipsychotics include generics clozapine, olanzapine, aripiprazole, risperidone, paliperidone, asenapine, and quetiapine fumarate (e.g. U.S. brand names Risperdal, Clozaril, Zyprexa, Abilify, Invega, Saphris and Seroquel).

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 antipsychotics 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 psychosis, 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 aspect of the brain that antipsychotics treat or cure. (For more information, read ICI’s “How Mental Disorders are Diagnosed” and “How Psychiatric Drugs are Researched and Marketed”.)

Antipsychotics 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 many medical and mental health professionals to state that antipsychotic drugs work by “blocking a specific subtype of the dopamine receptor”.

This is certainly part of what antipsychotics 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 the most up-to-date, definitive medical descriptions for the mechanisms of action of all of the antipsychotic drugs that are 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 antipsychotic drugs might affect some people diagnosed with mental disorders in “therapeutic” ways are “unknown”. 

It is known that antipsychotics disrupt and alter the functioning of a number of important neurotransmitters in a myriad of complex ways. Neurotransmitters are chemical messengers that play key roles in the basic communications and functional systems in the human body and brain. In recent years, most explanations of antipsychotic drug action have focused attention on the way these drugs disrupt the functioning of the neurotransmitter dopamine; however, antipsychotics also significantly affect the activities of the neurotransmitters serotonin, acetylcholine, histamine and others. These neurotransmitters are centrally involved in many key body and brain functions including behavior, arousal, cognition, memory, emotions, learning, pleasure, fine motor control, motivation, gastrointestinal function, endocrine and hormonal system functioning, and more. This is why antipsychotics can produce such a wide range of effects and side effects. Generally, the ways in which antipsychotics exert their effects on the brain and body are varied, complex, and poorly understood – especially as these effects start to change over time as the body adapts to the presence of the drugs.

Many users report that one of the main immediate effects of antipsychotic drugs is tranquilization, or a mild-to-strong slowing down of the body, often combined with a dulling or flattening of sensation, thought, emotions and experience. For some people, this tranquilizing or numbing effect can help reduce the intensity or frequency of some of the experiences that they are finding distressing. In other words, it is possible that some of the most common side effects of antipsychotics are for some people the primary means by which these drugs “work”.

Related reading:

Allison, Laura, and Joanna Moncrieff. “‘Rapid Tranquillisation’: An Historical Perspective on Its Emergence in the Context of the Development of Antipsychotic Medications.” History of Psychiatry 25, no. 1 (March 1, 2014): 57–69. doi:10.1177/0957154X13512573.

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.

According to the evidence provided to the FDA, antipsychotics seem to be effective for a few weeks to a few months at slightly reducing the frequency or intensity of some of the experiences associated with a diagnosis of Schizophrenia or psychosis. 

As a representative example, in 2002 the atypical antipsychotic aripiprazole (Abilify) was approved by the FDA for the short-term treatment of Schizophrenia on the basis of five clinical trials. Two of those trials actually showed that aripiprazole was not more effective than placebo pills (pills that have no medical effect), but the other three trials showed that aripiprazole was slightly more effective than placebo.

The three successful trials for Abilify were all 4-6 weeks in length. Participants’ symptoms were measured using a simple questionnaire. (For more information, see ICI’s “How Outcomes are Measured in Psychiatric Research”.) At the end of the trials, on a 210-point questionnaire rating the levels of intensity of a wide range of possible experiences associated with diagnoses of Schizophrenia like anxiety, delusions, poor attention, etc., the people taking Abilify scored on average only about 9 points lower (or “better”) than the people taking placebo. On a 7-point scale measuring the patients’ overall condition, people taking Abilify scored on average just about 0.3 points lower than people taking placebo pills.

The FDA’s medical review of these trials showed how even this level of drug effectiveness was likely even weaker than it appeared to be:

• The selection of trial participants was strongly biased in favor of the drug, because all of the participants were already identified before the trial began as good responders to antipsychotic drugs. In addition, people who did not tolerate aripiprazole well right away were removed from the trials and not counted.
• When calculating the final results, the researchers assumed that the condition of the people taking placebo who’d left the trial early would have worsened if they’d stayed in the trials. The drug achieved statistically significant superiority over placebo only when that assumption was factored in. On the contrary, though, the people in the placebo group who did stay in the trials started to improve, and by the end of the trials they did not generally have significantly worse scores than the people taking the drug.
• The people taking the drug experienced many more adverse effects such as heart attacks and abnormal heart rhythms, seizures, pneumonia, hypertension, hypotension, nausea, vomiting, akathisia and tremors. However, these effects were not relevant to the measuring of the drug’s effectiveness at reducing some of the specific experiences and behaviors associated with a diagnosis of Schizophrenia.

Based on these clinical trials, the FDA allowed the pharmaceutical company to publicly promote that Abilify is effective in treating people diagnosed with Schizophrenia.

These Abilify trials were not unusual; these very modest levels of effectiveness are typical for antipsychotics. For example, a meta-analysis of 105 clinical trials over three decades published in JAMA Psychiatry in 2014 found that patients diagnosed with Schizophrenia who took antipsychotics typically lowered their scores on symptom-measurement scales by only about 6 points more out of 108 points than patients taking placebo. The study authors also noted that, as these clinical trials continued past 12 weeks in duration, the drug groups typically worsened compared to the placebo groups.

And a similar study using a different approach was published in the American Journal of Psychiatry in 2017. The authors analyzed 60 years of placebo-controlled trials for Schizophrenia and found that people taking antipsychotic drugs typically lowered their symptom scores by only about 9.6 points more than people taking placebo, out of 210 possible points.

These short-term, limited levels of effectiveness of antipsychotics are important to understand when trying to appropriately weigh these drugs’ potential benefits against their potential harms.

Related reading:

Rutherford BR, Pott E, Tandler JM, Wall MM, Roose SP, and Lieberman JA. “Placebo Response in Antipsychotic Clinical Trials: A Meta-Analysis.” JAMA Psychiatry 71, no. 12 (December 1, 2014): 1409–21. doi:10.1001/jamapsychiatry.2014.1319.

Leucht, Stefan, Claudia Leucht, Maximilian Huhn, Anna Chaimani, Dimitris Mavridis, Bartosz Helfer, Myrto Samara, et al. “Sixty Years of Placebo-Controlled Antipsychotic Drug Trials in Acute Schizophrenia: Systematic Review, Bayesian Meta-Analysis, and Meta-Regression of Efficacy Predictors.” American Journal of Psychiatry, May 25, 2017, appi.ajp.2017.16121358. doi:10.1176/appi.ajp.2017.16121358.

U.S. Food and Drug Administration. Abilify Medical Reviews. (November 15, 2002)

Some antipsychotic drugs have been approved by the FDA for slightly longer-term maintenance treatment of people diagnosed with Schizophrenia. As a representative example, aripiprazole (Abilify) was approved by the FDA for maintenance treatment of Schizophrenia on the basis of one trial that lasted only about six months. In the trial, a relapse was defined to have occurred if a person’s general symptoms appeared to worsen at least minimally at any time, or if the person became very uncooperative, or if the person’s scores worsened by about 20 points on a 210-point questionnaire. During the 26-week trial, 49% of the people taking placebo experienced one of these kinds of relapses, while 27% of the people taking the drug experienced such a relapse.

The FDA’s medical review showed how the results of this trial were even weaker than they appeared:

• The selection of participants was strongly biased in favor of the drug, because all of the participants had been previously identified as having a history of being relatively good responders to antipsychotic drugs.
• All of the participants had been taking antipsychotics for at least two years, but at the start of the trial they were required to abruptly stop taking them before they were given Abilify or placebo. Therefore, it is likely that many of the participants – but especially people in the placebo group – began suffering drug withdrawal symptoms and were more likely than normal to experience serious adverse events and relapses.
• After the first two months, there was virtually no difference between the drug and placebo groups in the rates of relapses that were occurring.
• Virtually all of the relapses in both groups happened within the first four months, and after that both the placebo and the drug groups became equally stable.
• Even though many of the people in the placebo group would likely have been experiencing symptoms of psychiatric drug withdrawal, the people in the drug group still experienced higher rates of adverse effects such as vomiting, nausea, diarrhea, tremors, akathisia, insomnia and urogenital problems. However, these effects were not relevant to the measuring of the drug’s effectiveness at specifically postponing mental-emotional relapses.

These results were enough for the FDA to allow the drug company to state that Abilify is effective as a maintenance treatment for people diagnosed with Schizophrenia.

When trying to weigh the potential benefits and risks of taking antipsychotics for long periods of time, it’s important to understand this general lack of evidence for the drugs’ effectiveness over long-term use. Indeed, though many people who go on antipsychotics take the drugs for many years, as of 2016 only two studies of over 7 years in duration have ever been done. And both of these studies (see references below) generally indicated that people diagnosed with Schizophrenia or psychosis who take antipsychotics fare worse overall than people who either never take or eventually stop taking antipsychotics. In these studies, those people who took antipsychotics for very long periods were found, for example, to have more anxiety and worse cognitive impairment, and to be less likely to be functioning effectively in their lives or employed.

Related reading:

Harrow, M., T. H. Jobe, and R. N. Faull. “Do All Schizophrenia Patients Need Antipsychotic Treatment Continuously throughout Their Lifetime? A 20-Year Longitudinal Study.” Psychological Medicine 42, no. 10 (October 2012): 2145–55. doi:10.1017/S0033291712000220.

Wunderink L, Nieboer RM, Wiersma D, Sytema S, and Nienhuis FJ. “Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/Discontinuation or Maintenance Treatment Strategy: Long-Term Follow-up of a 2-Year Randomized Clinical Trial.” JAMA Psychiatry 70, no. 9 (September 1, 2013): 913–20. doi:10.1001/jamapsychiatry.2013.19.

For additional scientific references and a concise overview of the long-term research on antipsychotics as of 2016, see "The Case Against Antipsychotics" by medical journalist Robert Whitaker.

Some antipsychotics have been approved by the FDA to treat people diagnosed with Bipolar Disorder. According to the evidence provided to the FDA, these antipsychotics seem to be effective at slightly reducing the intensity or frequency of some of the experiences linked to Bipolar Disorder for periods of a few weeks to a few months.

As a representative example, in 2015, the FDA approved the antipsychotic drug Saphris (asenapine) for the treatment of children and youth diagnosed with Bipolar Disorder on the basis of just one clinical trial that lasted only three weeks. According to the drug label for Saphris, in this trial, on a 60-point questionnaire assessing issues like how quickly the children spoke, how animated they were, and whether they agreed that they needed medications, children taking Saphris scored about 3-6 points lower than children taking placebo pills. Meanwhile, compared to those taking placebo, the children taking Saphris experienced much higher rates of adverse effects such as numbness, tingling and pricking, fatigue, sedation and somnolence, but these increases in adverse effects were not relevant to the measuring of the effectiveness of the drug at reducing some of the specific experiences and behaviors associated with a diagnosis of Bipolar Disorder.

These findings were enough for the FDA to allow the drug company to state that Saphris is effective in treating pediatric Bipolar Disorder. These are fairly representative findings about the relative effectiveness of antipsychotics for people diagnosed with Bipolar Disorder. For example, Saphris was also approved for treating manic episodes in adults diagnosed with Bipolar Disorder on the basis of only two clinical trials lasting just three weeks, where the people taking the drug scored about 4.5 points lower than people taking placebo, on a questionnaire out of 60 total points.

When trying to weigh the potential benefits and harms of taking antipsychotics, it’s important to understand these short-term, very modest levels of effectiveness of the drugs in treating people diagnosed with Bipolar Disorder.

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.

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”.)

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

Since antipsychotics disrupt or alter the activities of neurotransmitters involved in many of the body’s primary functional and communications systems, including the nervous, endocrine, cardiovascular, digestive, metabolic, reproductive, and other systems, the list of possible harmful effects even in short-term use is very long. Antipsychotics are often considered to be one of the more risky types of drugs that are prescribed for non life-threatening conditions.  

When they were first introduced, it was often claimed that newer, atypical antipsychotics had fewer side effects than older, typical antipsychotics, but for the most part these claims have not held up to independent scientific investigation. However, there are sometimes important differences between particular antipsychotic drugs in terms of their adverse effects – it is always important to read the drug labels. A selection of some of the more significant possible adverse effects of antipsychotics that can emerge within days or weeks of beginning to take the drugs include:

• Metabolic changes and mild to severe weight gain.
• Feeling sedated and physically and mentally slow.
• Feeling disengaged, separated from the world, numb, or no longer creative.
• Suicidal thoughts and feelings.
• Loss of libido or sexual dysfunction.
• Headache, dry mouth, blurred vision, and gastrointestinal disorders.
• Convulsions or seizures.
• Tardive dyskinesia (motor dysfunction or loss of motor control) and Parkinsonism.
• Akathisia, or mild-to-extreme restlessness and agitation.
• Heart disease, strokes, heart malfunction, and death.
• Neuroleptic malignant syndrome, and death.

Some of these and other adverse effects are described in more detail below.

Related reading:

Moore, Thomas J., and Curt D. Furberg. “The Harms of Antipsychotic Drugs: Evidence from Key Studies.” Drug Safety, November 19, 2016. doi:10.1007/s40264-016-0475-0.

Üçok, Alp, and Wolfgang Gaebel. “Side Effects of Atypical Antipsychotics: A Brief Overview.” World Psychiatry 7, no. 1 (February 2008): 58–62.

Muench, J and Ann Hamer. "Adverse Effects of Antipsychotic Medications." American Family Physician. 2010 Mar 1;81(5):617-622.

According to their drug labels, all antipsychotics cause disruptions to the body’s normal weight regulation. Weight gain of approximately 10-45 pounds (approximately 5-20 kilograms) within several months of beginning an antipsychotic for the first time is common. Weight gain tends to continue over the long term, though less rapidly. It is not fully understood what causes it, but these changes are not solely the result of people eating more or eating poorly while taking antipsychotics; the drugs seem to fundamentally disrupt the body’s normal metabolic processes.

Related reading:

Bak, Maarten, Annemarie Fransen, Jouke Janssen, Jim van Os, and Marjan Drukker. “Almost All Antipsychotics Result in Weight Gain: A Meta-Analysis.” PLoS ONE 9, no. 4 (April 24, 2014). doi:10.1371/journal.pone.0094112.

Antipsychotics are not known to cause Parkinson’s disease, but they are known to cause many similar effects to Parkinson’s. Tardive dyskinesia is a motor dysfunction characterized by trembling, shaking, or other uncontrollable movements such as frequent leg-vibrating, excessive eye blinking, or intermittent lip smacking or tongue wagging. Tardive dyskinesia is caused by neurological damage, and is a common effect of antipsychotic drugs that is listed in their drug labels. It is often, but not always, permanent and irreversible.

Rates vary, but studies show that the likelihood of getting tardive dyskinesia increases with the length of time a person takes an antipsychotic. After one year of taking an antipsychotic, about 1-7% of people develop tardive dyskinesia. After five years, the rate increases to more than 30%.

It is sometimes claimed that newer, atypical antipsychotics are less likely to cause tardive dyskinesia than older, typical antipsychotics, but studies show that the differences in rates, if any, seem to be small.

Related reading:

Glazer, W. M., H. Morgenstern, and J. T. Doucette. “Glazer WM, Morgenstern H, Doucette JT. Predicting the Long-Term Risk of Tardive Dyskinesia in Outpatients Maintained on Neuroleptic Medications. J Clin Psychiatry 54: 133-139.” ResearchGate 54, no. 4 (May 1, 1993): 133–39.

Miller, Del D., Stanley N. Caroff, Sonia M. Davis, Robert A. Rosenheck, Joseph P. McEvoy, Bruce L. Saltz, Silvana Riggio, et al. “Extrapyramidal Side-Effects of Antipsychotics in a Randomised Trial.” The British Journal of Psychiatry: The Journal of Mental Science 193, no. 4 (October 2008): 279–88. doi:10.1192/bjp.bp.108.050088.

Woerner, Margaret G., Christoph U. Correll, Jose Ma J. Alvir, Blaine Greenwald, Howard Delman, and John M. Kane. “Incidence of Tardive Dyskinesia with Risperidone or Olanzapine in the Elderly: Results from a 2-Year, Prospective Study in Antipsychotic-Naïve Patients.” Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 36, no. 8 (July 2011): 1738–46. doi:10.1038/npp.2011.55.

Woods, Scott W., Hal Morgenstern, John R. Saksa, Barbara C. Walsh, Michelle C. Sullivan, Roy Money, Keith A. Hawkins, Ralitza V. Gueorguieva, and William M. Glazer. “Incidence of Tardive Dyskinesia with Atypical versus Conventional Antipsychotic Medications: A Prospective Cohort Study.” The Journal of Clinical Psychiatry 71, no. 4 (April 2010): 463–74. doi:10.4088/JCP.07m03890yel.

Akathisia is a term used to describe a sense of physical and mental restlessness and agitation that can range from relatively mild to so intense as to induce self-harm or even violent rages. Akathisia is a common side effect of antipsychotic drugs that is identified in their drug labels. Studies have shown that anywhere from 8% to 45% of people who take antipsychotics will suffer from some level of akathisia. The effect can come and go for periods of time, or it can be an almost constant sensation.

Abruptly stopping antipsychotics can also produce drug withdrawal effects, including extreme, unrelenting akathisia that can lead to self-harm or acts of physical violence. (See below for more information about dependence and withdrawal.)

Related reading:

Poyurovsky, Michael. “Acute Antipsychotic-Induced Akathisia Revisited.” The British Journal of Psychiatry 196, no. 2 (February 1, 2010): 89–91. doi:10.1192/bjp.bp.109.070540.

It has often been claimed that certain psychiatric diagnoses such as schizophrenia are associated with specific alterations in the brain; however, this research has always been confounded by the fact that studies of the issue have typically involved patients who have previously taken antipsychotic medications. Antipsychotics themselves have been shown to cause fundamental alterations in brain structure and reductions in the amount or volume of brain matter, especially over long-term use. For example, one 2011 study published in the Archives of General Psychiatry identified that greater dosages of antipsychotics over longer periods of time were associated with reductions in both brain gray matter and white matter.

Related reading:

Ho, Beng-Choon, Nancy C. Andreasen, Steven Ziebell, Ronald Pierson, and Vincent Magnotta. “Long-Term Antipsychotic Treatment and Brain Volumes: A Longitudinal Study of First-Episode Schizophrenia.” Archives of General Psychiatry 68, no. 2 (February 2011): 128–37. doi:10.1001/archgenpsychiatry.2010.199.

Torres, Ulysses S., Fabio L.S. Duran, Maristela S. Schaufelberger, José A.S. Crippa, Mario R. Louzã, Paulo C. Sallet, Caroline Y.O. Kanegusuku, et al. “Patterns of Regional Gray Matter Loss at Different Stages of Schizophrenia: A Multisite, Cross-Sectional VBM Study in First-Episode and Chronic Illness.” NeuroImage : Clinical 12 (June 3, 2016): 1–15. doi:10.1016/j.nicl.2016.06.002.

According to their drug labels, antipsychotic use is linked to significant increases in diabetes. The exact mechanisms by which diabetes may be caused are unknown, though research suggests that antipsychotic-induced weight gain plays a role, along with direct drug impacts on insulin resistance and insulin secretion. 

Different antipsychotics are associated with different rates, but generally when taking an antipsychotic people experience a 30% to 200% increase in their risk of developing diabetes. The risk of developing diabetes tends to increase in association with the length of time taking the drug, with higher doses, and with use of more than one antipsychotic at a time.

Related reading:

Kessing, Lars Vedel, Anders Frøkjær Thomsen, Ulla Brasch Mogensen, and Per Kragh Andersen. “Treatment with Antipsychotics and the Risk of Diabetes in Clinical Practice.” The British Journal of Psychiatry: The Journal of Mental Science 197, no. 4 (October 2010): 266–71. doi:10.1192/bjp.bp.109.076935.

Chhim, Theary, Phil Chase and Joshua J. Neumiller. “Antipsychotic-Induced Diabetes Mellitus.” US Pharmacist. 2012;37(11):39-44.

All drug labels for antipsychotics warn about neuroleptic malignant syndrome (NMS), a rapid-onset, life-threatening neurological disorder that can be caused by antipsychotic drugs. Early symptoms include high fever, sweating, and unstable blood pressure. Advanced symptoms can appear within several days and include stupor, muscular rigidity, autonomic dysfunction, a coma-like, permanent shutdown of the nervous system, and death. NMS most often develops within a month of first beginning to take an antipsychotic, but can develop at any time while taking one.

It is difficult to estimate the overall rate of NMS, because the rate seems to vary depending on dosage levels, length of time taking an antipsychotic, number of antipsychotics being taken, exactly how the condition is identified, and other unknown factors. However, some studies suggest that about 1 in 500 people who take an antipsychotic will develop NMS. Between 10% and 76% of people who develop NMS will die from it.

Related reading:

Berman, Brian D. “Neuroleptic Malignant Syndrome.” The Neurohospitalist 1, no. 1 (January 2011): 41–47. doi:10.1177/1941875210386491.

Pelonero, Anthony L., James L. Levenson, and Anand K. Pandurangi. “Neuroleptic Malignant Syndrome: A Review.” Psychiatric Services 49, no. 9 (September 1, 1998): 1163–72. doi:10.1176/ps.49.9.1163.

Strawn, Jeffrey R, Paul E. Keck Jr. and Stanley N. Caroff. "Neuroleptic Malignant Syndrome: Answers To 6 Tough Questions." Malignant Hyperthermia Association of the United States. (Accessed May 23, 2017.)

According to their drug labels, antipsychotics have not been adequately tested to establish their safety for use during pregnancy. The wide range of potentially harmful adverse effects of antipsychotics -- particularly on basic metabolic and neurological processes -- suggest that it is extremely likely that the drugs could be harmful to fetuses.

In addition, according to their drug labels, the infants of mothers who take antipsychotics during pregnancy can sometimes suffer severe drug withdrawal effects, including “agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding.”

All antipsychotics raise levels of macroprolactin and prolactin in the body – a condition called hyperprolactinemia. This can lead to a small percentage of boys and men growing larger breasts, which is called gynecomastia. This adverse effect is listed in some drug labels, but there are few studies showing exactly how common gynecomastia is. It appears that some antipsychotics are more likely than others to lead to breast growth. In some situations, drug-induced breast enlargement is persistent and irreversible, and can only be removed through surgery. In females, hyperprolactinaemia can cause lactation, loss of libido, and bone density loss.

Related reading:

Park, Young-Min, Seung-Hwan Lee, Bun-Hee Lee, Kyu Young Lee, Kye-Seong Lee, Seung-Gul Kang, Hwa-Young Lee, and Won Kim. “Prolactin and Macroprolactin Levels in Psychiatric Patients Receiving Atypical Antipsychotics: A Preliminary Study.” Psychiatry Research 239 (May 30, 2016): 184–89. doi:10.1016/j.psychres.2016.03.015.

All of the antipsychotics come with warnings in their drug labels that these drugs are associated with significant increases in death rates under some conditions. In elderly people with dementia, for example, antipsychotics are linked to a near doubling of the death rate within six months of starting the drugs. For people of all ages, antipsychotics have been linked to a tripling of heart attack-related deaths. The risk of death increases with the drug dose.

If taking or not taking an antipsychotic leads to lifestyle changes, those changes of course could lower or raise a person’s risk of death as well.

Related reading:

Maust DT, Kim H, Seyfried LS, and et al. “Antipsychotics, Other Psychotropics, and the Risk of Death in Patients with Dementia: Number Needed to Harm.” JAMA Psychiatry 72, no. 5 (May 1, 2015): 438–45. doi:10.1001/jamapsychiatry.2014.3018.

Straus SM, Bleumink GS, Dieleman JP, et al. “Antipsychotics and the Risk of Sudden Cardiac Death.” Arch Intern Med. 2004;164(12):1293-1297. doi:10.1001/archinte.164.12.1293

Some research suggests that the long-term interference in the brain’s internal communications and functional systems by antipsychotics can lead to the brain developing a compensatory response. The brain, for example, can apparently grow new neurotransmitter receptors and/or develop heightened sensitivity to certain neurotransmitters as an adjustment to an antipsychotic drug’s particular neurotransmitter-blocking actions. Some researchers describe this as the development of drug-induced supersensitivity in the brain, and it is believed to be at least part of the reason that antipsychotic effectiveness tends to diminish over time. (See below for more information on tolerance, dependence, and withdrawal.)

This drug-induced, heightened sensitivity may also be a factor leading to conditions that researchers call transient rebound psychosis and supersensitivity psychosis, in which experiences such as paranoia, hallucinations and unusual beliefs can start to emerge for the first time or much more intensely than ever before when antipsychotics begin to lose their effectiveness, are decreased in dose, or are suddenly stopped completely. Some researchers suggest that this may be a person’s underlying problems re-emerging; however, there is evidence that people with no history of psychosis or mental health problems can sometimes have psychotic experiences while undergoing antipsychotic withdrawal, and that people who’ve previously had psychotic experiences can have much more intense experiences than they had before starting on antipsychotics.

Related reading:

Chouinard, G., and B. D. Jones. “Neuroleptic-Induced Supersensitivity Psychosis: Clinical and Pharmacologic Characteristics.” The American Journal of Psychiatry 137, no. 1 (January 1980): 16–21. doi:10.1176/ajp.137.1.16. (Also available here.)

Oda, Yasunori, Nobuhisa Kanahara, and Masaomi Iyo. “Alterations of Dopamine D2 Receptors and Related Receptor-Interacting Proteins in Schizophrenia: The Pivotal Position of Dopamine Supersensitivity Psychosis in Treatment-Resistant Schizophrenia.” International Journal of Molecular Sciences 16, no. 12 (December 17, 2015): 30144–63. doi:10.3390/ijms161226228.

Yin, John, Alasdair M. Barr, Alfredo Ramos-Miguel, and Ric M. Procyshyn. “Antipsychotic Induced Dopamine Supersensitivity Psychosis: A Comprehensive Review.” Current Neuropharmacology, June 5, 2016.

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.

Antipsychotics are not considered to be addictive drugs. They do not induce “cravings” after a period of regular use. However, antipsychotics are known to be dependence-forming. This means that, over time, the body and brain adjust and adapt to the presence of the drugs, and people can experience a wide variety of difficult or even dangerous withdrawal symptoms when they abruptly stop taking them. This is sometimes called “discontinuation syndrome”.

As of 2017, many of the drug labels for antipsychotics mentioned the possibility of experiencing discontinuation syndrome or withdrawal symptoms after abruptly stopping the drugs. Nearly all of the labels specifically caution that infants borne to mothers taking antipsychotics have been observed to experience mild-to-severe, and sometimes long-lasting drug withdrawal symptoms. Withdrawal symptoms caused by suddenly stopping are widely reported by people who have withdrawn from antipsychotics.

It is not fully understood how antipsychotics affect the body and brain, and so it is also not understood exactly how sudden discontinuation of these drugs after periods of regular use can produce a wide range of mild-to-severe drug withdrawal symptoms. However, it is known that antipsychotics at least initially reduce or “apply the brakes to”, for example, the activities of the neurotransmitter dopamine. And there is evidence that, over time, the body compensates for this situation by pressing its own internal dopamine “gas pedal” – the body and brain undergo physical changes that increase sensitivity to dopamine and/or increase the production of dopamine. So what happens when the antipsychotic-induced braking suddenly disappears? That is, when the drug is abruptly stopped and its dopamine braking is therefore also abruptly stopped – and this occurs while the brain and body are still pressing their own internal dopamine gas pedals – what happens? Further, antipsychotics affect not only the activities of dopamine, but the activities of many other neurotransmitters as well. 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?

Common reported symptoms of antipsychotic drug withdrawal include nausea, eating problems, vomiting, headaches, somnolence and insomnia. More serious reported symptoms include agitation, tremors, anxiety, emotional swings, motor dysfunction, and mild-to-severe inner restlessness and agitation. In infants born to mothers who were taking antipsychotics, muscular rigidity, muscular floppiness, and severe respiratory distress have also been observed.

There have been no large, formal scientific studies into the symptoms of antipsychotic withdrawal or 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.)