"Mood Stabilizers" and Lithium

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?

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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 Inner Compass Initiative'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, 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.

Some drugs are grouped into classes because they have chemical similarities, such as benzodiazepines (e.g. Ativan, Valium, Xanax etc.) or stimulants (e.g. Ritalin, Adderall etc.). The term “mood stabilizer”, though, was popularized during the 1990s mainly as a marketing tool, and does not represent a scientific grouping of drugs in the way that scientific classes are ordinarily understood. However, because the name “mood stabilizer” conjured images of a medicine that had the ability to target and stabilize out-of-control emotions, it captured the medical and popular imagination and ever since has been applied to a wide variety of new and older psychotropic drugs.

Drugs that are sometimes referred to as "mood stabilizers" include:

1. The naturally occurring mineral lithium, including lithium carbonate and lithium citrate (e.g. U.S. brand name Lithobid).
2. Anticonvulsant drugs generally used for helping prevent epileptic seizures, including carbamezapine, lamotrigine, valproate or valproic acid, gabapentin, and topiramate (e.g. U.S. brand names Equetrol, Lamictal, Depakote, Depakene, Neurontin, Topamax).
3. Antipsychotics like asenapine, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, and clozapine (e.g. U.S. brand names Saphris, Zyprexa, Seroquel, Risperdal, Abilify, Geodon, Clozaril). 

A psychiatrist or physician most often chooses to describe a drug as a “mood stabilizer” when he or she is prescribing the drug to a person who has been given a diagnosis of a psychological problem involving difficulty with emotions or impulses. Mood stabilizers are often prescribed, for example, to people who’ve been given diagnostic labels of Bipolar Disorder, Major Depressive Disorder, Generalized Anxiety Disorder, or Schizophrenia. Many of these drugs are not approved by the U.S. Food and Drug Administration for these purposes, but some psychiatrists and physicians prescribe them “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”.)

Please read ICI’s mini-booklet "Antipsychotics” for more about that class of drugs. This page focuses on lithium and anticonvulsant drugs.

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 psychiatric “mood stabilizer” drugs like lithium and anticonvulsants work, because the word “work” implies that the drugs have a well-understood effect on a discrete area or pathway in the brain involved in creating extremes of moods, or a curative action on 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 or emotions that these drugs treat or cure. (For more information, read ICI’s “How Mental Disorders are Diagnosed” and “How Psychiatric Drugs are Researched and Marketed”.)

Mood stabilizers 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 make claims that lithium and anticonvulsant drugs “balance certain brain chemicals” or “bring stability and calm to areas of the brain that have become overstimulated and overactive”.

These kinds of characterizations resemble promotional advertisements for drugs more than factual statements. The U.S. Food and Drug Administration and pharmaceutical manufacturers have developed the most up-to-date, definitive medical descriptions for the mechanisms of action of lithium and all of the anticonvulsant 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 Inner Compass Initiative's Guide to the FDA-approved Drug Labels”.) According to these explanations, the biological mechanisms by which lithium and anticonvulsant drugs might affect some people diagnosed with mental disorders in “therapeutic” ways “have not been established” and are “unknown”.

It is known that, in part, lithium and anticonvulsant drugs disrupt and alter basic sodium channel activity and sodium transport operations in human nerve and muscle cells. They also disrupt and alter the functioning of a number of important chemical messengers in the basic communications and functional systems of the brain and body, including the neurotransmitters glutamate, GABA (gamma-aminobutryic acid), norepinephrine and serotonin. This in turn creates impacts in the central nervous system, including in neuromuscular, neurological and cognitive processes. This is why lithium and anticonvulsant drugs can produce such a wide range of effects and side effects such as blurry vision, tremors, memory impairment, and kidney damage, and why the ways in which these drugs affect the body and brain are beyond our current level of scientific understanding – especially as their effects can start to change over time as the body adapts to the presence of the drugs.

Many users report that lithium and anticonvulsants often produce feelings of mild-to-strong sedation and mental blunting or numbing. For some people, these effects can help reduce the intensity and frequency of the feelings and experiences associated with “mania”. In other words, it is possible that some of the commonly recognized side effects of lithium and anticonvulsants are for some people the primary means by which these drugs “work”.

Related reading:

Price, Lawrence H., and George R. Heninger. “Lithium in the Treatment of Mood Disorders.” New England Journal of Medicine 331, no. 9 (September 1, 1994): 591–98. doi:10.1056/NEJM199409013310907.

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.

Many anticonvulsant drugs have not been approved by the FDA for use in the United States for the treatment of people diagnosed with any mental disorders. Though some physicians and psychiatrists describe anticonvulsants as “mood stabilizers” and prescribe them off-label to treat people diagnosed with a variety of mental disorders, most of these drugs are not considered to be either effective or safe for these uses by U.S. health regulators. As of 2017, only lithium and a small number of anticonvulsant drugs – including Lamictal, Depakote and Equetro – have been approved for treating people diagnosed with Bipolar Disorder, and even then only for very specific uses as described below.

Lithium was determined to be so toxic to humans and lacking in clinical usefulness that it was banned from all food and medical uses by the FDA in the 1940s. However, in 1970 lithium was approved specifically and only for use on people diagnosed with mania or Bipolar Disorder. It is the only drug approved by the FDA as a long-term treatment for people diagnosed with Bipolar Disorder.

The scientific evidence provided to the FDA to establish lithium’s effectiveness in mania or Bipolar Disorder is limited. Though the approval occurred in 1970, physicians and psychiatrists had already been prescribing the drug without FDA approval. The official approval was largely based on evidence that people diagnosed with Bipolar Disorder who’d been taking lithium for many years became slightly more likely to experience some kind of emotional problem or relapse when they were abruptly taken off the lithium. According to a 2004 systematic review and meta-analysis of long-term lithium studies that was published in the American Journal of Psychiatry, people taking lithium seemed to be about 20% less likely to have a more serious mood episode or relapse than people taking placebo pills, and 10% less likely to have a manic episode than people taking placebo. The authors noted that this in effect meant that for every 10 people treated with lithium continually for 1-2 years, about 1 or 2 of those people might avoid one serious mood episode. Lithium was not found to significantly reduce depressive feelings.

When trying to appropriately weigh the potential benefits of lithium against its potential harms, it’s important to clearly understand and consider these limited effectiveness rates.

And many reviewers have raised concerns about the reliability of even this limited evidence for lithium’s effectiveness. This is because essentially all of the longer-term, randomized controlled trials ever done comparing lithium and placebo have involved participants who were for the most part already taking psychiatric drugs – including lithium – for months or years before the trials began. This makes it very possible that all of the placebo groups had more emotional difficulties and higher relapse rates in part due to the fact that these people were likely suffering from symptoms of drug withdrawal (see below for more information about the dependence-forming nature of lithium). Indeed, in some of the lithium trials, the relapse rates in the placebo groups dropped significantly when people were withdrawn more slowly, or once these participants had a period of time to adjust to being without the drugs. As of 2017, there have still been no long-term, randomized, placebo-controlled clinical trials that evaluate the effectiveness of lithium in treating people diagnosed with Bipolar Disorder who were not already taking lithium or other psychiatric drugs before the trial began.

Related reading:

Burgess, Sally SA, John Geddes, Keith KE Hawton, Matthew J Taylor, Ellen Townsend, K Jamison, and Guy Goodwin. “Lithium for Maintenance Treatment of Mood Disorders.” In Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd, 2001.

Geddes, John R., Sally Burgess, Keith Hawton, Kay Jamison, and Guy M. Goodwin. “Long-Term Lithium Therapy for Bipolar Disorder: Systematic Review and Meta-Analysis of Randomized Controlled Trials.” American Journal of Psychiatry 161, no. 2 (February 1, 2004): 217–22. doi:10.1176/appi.ajp.161.2.217.

Moncrieff, J. “Reasons not to believe in lithium.” (JoannaMoncrieff.com.) July 1, 2015.

According to the evidence presented to the FDA and summarized in its drug label, Depakote (valproate or divalproex sodium) seems to be effective for a period of a few weeks at slightly reducing the intensity or frequency of some of the “manic” experiences linked to a diagnosis of Bipolar Disorder.

Depakote was approved for treating people diagnosed with acute manic episodes and Bipolar Disorder on the basis of just two clinical trials lasting only three weeks. In the first trial, people who’d been hospitalized with a diagnosis of acute mania were given either Depakote or a placebo pill (a pill that has no medical effects). Psychiatrists then scored the patients from 0 to 4 or 0 to 8 on questions addressing issues like the patients’ apparent levels of irritability, the relative speed of their talking, and how fully they agreed with the physician that they had a mental disorder. (For more information, see ICI’s “How Outcomes are Measured in Psychiatric Research”.) In one of the two studies, on a questionnaire out of 63 total points, people taking Depakote scored 5.1 points lower than people taking placebo. In the second study, on a questionnaire out of 60 total points, people taking Depakote scored on average 9.7 points lower (or “better”) than people taking placebo, and on another questionnaire out of 100 total points, people taking Depakote scored on average 18.1 points lower. Roughly combining the above scores, overall, people taking Depakote appeared to be about 12% ‘less manic’ than people taking placebo. There was no evidence that people’s depressed feelings or lower moods improved.

Meanwhile, the people in the two trials who were taking Depakote experienced many more adverse effects such as gastrointestinal problems, sedation, increased appetite with weight gain, tremors, and motor control problems – but these effects were not relevant to the measuring of the effectiveness of Depakote at reducing specific types of manic feelings associated with a diagnosis of Bipolar Disorder.

The results of these two trials were enough for the FDA to allow the drug company to state that Depakote is effective in treating manic episodes linked to Bipolar Disorder. Depakote was not approved for treating people diagnosed with Bipolar Disorder generally or for being used for longer than three weeks.

When trying to appropriately weigh the potential benefits of Depakote against its potential harms, it’s important to clearly understand and consider this limited effectiveness.

According to the evidence provided to the FDA, Lamictal (lamotrigine) is effective at slightly lengthening the amount of time between certain kinds of mood episodes experienced by people diagnosed with Bipolar Disorder.

Lamictal received this approval from the FDA on the basis of just two clinical trials lasting about 18 months in total. In the two trials, people diagnosed with Bipolar Disorder were given either Lamictal, lithium or placebo pills. The researchers then measured the amount of time it took before the patients experienced a “mood episode” or “adverse bipolar event”. The drug company and FDA separately performed mathematical calculations on the findings in a dozen different ways, but on average, people taking placebo seemed to go about two months before such an event occurred, while people taking Lamictal went about three months, and people taking lithium went about four months.

The FDA medical review highlighted many reasons why these results were even weaker than they appeared:

• Eight previous clinical trials had been conducted trying to demonstrate that Lamictal was effective in treating Bipolar Disorder and depression, and Lamictal had consistently failed. The FDA medical review described it as “an unusual circumstance in psychiatry” and “novel” that the pharmaceutical company was now trying to get Lamictal approved for long-term management of Bipolar Disorder, when the drug had consistently failed to show effectiveness for short-term use.
• The selection of participants for these two new trials were biased in favor of Lamictal, because people were only included in the trials if they had already been identified as good responders to Lamictal. In addition, people who could not be stabilized on Lamictal for at least four weeks beforehand were removed from the trials.
• The key definition of which kinds of events during the trials would qualify as a relapse, crisis, “mood episode” or “adverse bipolar event” was never clear to the FDA, because the researchers kept amending and changing this definition of what the study was supposed to be measuring. In fact, after the study was concluded, the researchers changed the definition of what kind of event qualified as a relapse or mood episode yet again. The FDA allowed the change, but noted that, based on the original definitions, Lamictal would have failed in both trials.
• At the beginning of both trials, about 80% of the people were already taking one or more psychiatric drugs, and they were all forced to stop taking these drugs over a two-week period. Therefore, it is likely that many of the participants – but particularly those in the placebo group since they were suddenly getting no drugs at all – were suffering acute drug withdrawal symptoms and were more likely than normal to experience an adverse event or mood episode of some kind. Indeed, the FDA noted that about 40% of the participants had to abruptly withdraw from benzodiazepine sedatives, which are known to be strongly dependence-forming and prone to producing extremely difficult withdrawal symptoms. (For more information, see ICI’s mini-booklet “Anti-Anxiety” Benzodiazepines.)

Nevertheless, these results were enough for the FDA to allow the drug company to state that Lamictal is effective in helping to “delay the time to occurrence of mood episodes” in people diagnosed with Bipolar Disorder. There was no evidence that people’s depressed feelings/moods improved.

When trying to appropriately weigh the potential benefits of Lamictal against its potential harms, it’s important to clearly understand and consider these limited effectiveness rates.

Related reading:

U.S. Food and Drug Administration. “Medical Review: Lamictal.” (June, 2003)

None of the anticonvulsant drugs have been approved by the FDA as effective for long-term use in treating people diagnosed with Bipolar Disorder or any other mental disorders. Lithium has been approved for long-term use in treating people diagnosed with Bipolar Disorder but, as described above, the evidence provided to the FDA was limited.

Neither lithium nor any anticonvulsant drugs have been approved by the FDA as effective in any way for treating children diagnosed with Bipolar Disorder or any other mental disorder. When these drugs have been officially tested for the purposes of obtaining approval for treating children diagnosed with mental disorders, they have failed.

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 Inner Compass Initiative'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 Inner Compass Initiative'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

Lithium is extremely toxic to the human body, and can be very dangerous and potentially lethal at blood serum levels that are very close to the “therapeutic” levels that are commonly prescribed by psychiatrists. Therefore, when taking lithium, your blood must be tested frequently. Certainly this is most important when you are first initiating lithium use; however, its drug label warns that there are many other factors that could change the levels of lithium concentration in your blood and put you in greater danger. Use of other prescription or recreational drugs, diseases, levels of physical exercise, food and water consumption habits, and other lifestyle factors can significantly affect your body’s serum lithium levels. Consequently, frequent blood monitoring is very important, but especially when anything significant in your life or lifestyle changes even for short periods of time.

Some of the common adverse effects of lithium which are early signs of lithium toxicity include diarrhea, vomiting, drowsiness, muscular weakness, and lack of muscle coordination. More serious warning signs include giddiness, loss of muscle control, blurred vision, tinnitus and excessive urination. Lithium toxicity can also lead to tremors, apathy, drowsiness, slurred speech, confusion, seizures, coma and death.

Two of the most common adverse effects of lithium are excessive thirst and excessive urination. These are usually related to the development of a condition called nephrogenic diabetes insipidus, which involves damage to the kidneys.

Lithium is known to impair renal function and cause damage to the kidneys that generally becomes worse with higher doses or with longer-term use of the drug. It is important to understand that when lithium levels are found to be within the “appropriate” range based on blood tests, this means that the drug should not result in rapid death; however, mild, moderate or even severe toxicity may still be present and can worsen over time. In a 1994 study of long-term users of lithium in Sweden, kidney disease was found in nearly half of all patients. Even relatively low levels of chronic lithium toxicity can lead to a need for a kidney transplant.

Related reading:

Bendz, H., M. Aurell, J. Balldin, A. A. Mathé, and I. Sjödin. “Kidney Damage in Long-Term Lithium Patients: A Cross-Sectional Study of Patients with 15 Years or More on Lithium.” Nephrology Dialysis Transplantation 9, no. 9 (January 1, 1994): 1250–54.

The thyroid gland plays important roles in a number of metabolic, cardiovascular and developmental growth functions in the human body, and also in brain function, sexual function, sleep, emotions and thought. Lithium’s drug label includes specific warnings that thyroid function should be monitored frequently while taking the drug because lithium can cause permanent, irreversible damage to thyroid function.

Studies suggest that within 1-2 years of lithium use, 4% of people develop hypothyroidism, and the rates increase by about 1-2% a year over time. Women seem to be at higher risk than men. Damage can lead to a wide variety of problematic symptoms and the need to take thyroid replacement drugs.

Goiters are unusual enlargements of the thyroid gland, or tumors on the thyroid, that can sometimes become large protrusions on the neck. Goiters are a common side effect of lithium. Some studies have found that about 4% of people who take lithium will develop goiters, and that number increases by about 4% for every year of use.

Related reading:

Bocchetta, Alberto, and Andrea Loviselli. “Lithium Treatment and Thyroid Abnormalities.” Clinical Practice and Epidemiology in Mental Health : CP & EMH 2 (September 12, 2006): 23. doi:10.1186/1745-0179-2-23.

Bocchetta, A., F. Bernardi, M. Pedditzi, A. Loviselli, F. Velluzzi, E. Martino, and M. Del Zompo. “Thyroid Abnormalities during Lithium Treatment.” Acta Psychiatrica Scandinavica 83, no. 3 (March 1991): 193–98.

Some of the known side effects of lithium include ataxia (the loss of full control of bodily movements), blurry vision, foggy thinking, hand tremors, memory impairment, and problems with comprehension and learning, and these have been linked to irreversible brain damage that can be caused by the drug.

According to the drug label, combining lithium with an antipsychotic drug can also in some cases significantly affect blood serum levels of lithium and lead to weakness, lethargy, fever, confusion, movement disorders, glucose-level changes and other symptoms, “followed by irreversible brain damage.”

Related reading:

Schou, M. “Long-Lasting Neurological Sequelae after Lithium Intoxication.” Acta Psychiatrica Scandinavica 70, no. 6 (December 1984): 594–602.

Lithium can cause a condition called serotonin syndrome, a state involving hyper-activity in the serotonin neurotransmitter system. This can lead to a wide variety of physical and mental symptoms, including agitation, hallucinations and delirium. Serotonin syndrome is potentially life-threatening. The risk of developing serotonin syndrome while taking lithium alone seems to be very small but, according to its drug label, the risk of developing the syndrome is increased when lithium is combined with other drugs that impair the metabolism of serotonin such as antidepressants, cocaine, some dietary supplements, and certain painkilling drugs.

Lithium comes with strong warnings in its drug label about the potential harms to fetuses and infants when mothers take the drug during pregnancy and breastfeeding. For example, lithium use has been linked to birth defects such as cardiovascular malformations in humans, and in animal studies (at dose levels similar to the human therapeutic range) to increased skeletal abnormalities, increased fetal mortality, and decreased fetal weight. According to a 2014 review in Drug, Healthcare and Patient Safety, fetal heart defects alone occur at 20 times higher rates in mother’s taking lithium. The drug label also specifically recommends against taking lithium when breastfeeding. 

Depakote’s drug label gives strong warnings to pregnant mothers that the drug increases the risks of birth defects such as neural tube defects and other structural abnormalities like craniofacial defects, cardiovascular malformations, and limb malformations. It also leads to decreased intelligence scores in children born to mothers taking the drug.

According to the drug label for Lamictal, “There are no adequate and well-controlled studies in pregnant women.” In animal studies, Lamictal was found to be “developmentally toxic” to fetuses at doses lower than normal, comparable doses for humans, and associated with reduced fetal body weight, increased incidences of fetal skeletal problems, behavioral abnormalities and stillbirths. During breastfeeding, very high levels of Lamictal were found in infants.

According to an article in 2010 in the Expert Review of Neurotherapeutics, some of these birth defects associated with anticonvulsants occur at rates 10 to 20 times higher than in the general population. Overall, birth defects tend to be two to three times as high, occurring in about 6% of women taking an anticonvulsant.

Related reading:

Hill, Denise S, Bogdan J Wlodarczyk, Ana M Palacios, and Richard H Finnell. “Teratogenic Effects of Antiepileptic Drugs.” Expert Review of Neurotherapeutics 10, no. 6 (June 2010): 943–59. doi:10.1586/ern.10.57.

Epstein, Richard A, Katherine M Moore, and William V Bobo. “Treatment of Bipolar Disorders during Pregnancy: Maternal and Fetal Safety and Challenges.” Drug, Healthcare and Patient Safety 7 (December 24, 2014): 7–29. doi:10.2147/DHPS.S50556.

Many physicians and psychiatrists state that mood stabilizers reduce the likelihood of suicide, but the actual evidence from placebo-controlled, randomized studies do not support these claims. Indeed, Depakote and Lamictal come with specific warnings in their drug labels that they significantly increase suicidal thoughts and behaviors. And a 2004 systematic review of long-term lithium use published in the American Journal of Psychiatry found that, “Data from these randomized trials were insufficient to estimate the possible suicide prevention effect of lithium[.]”

Related reading:

Healy, David. “The Latest Mania: Selling Bipolar Disorder.” PLOS Med 3, no. 4 (April 11, 2006): e185. doi:10.1371/journal.pmed.0030185.

Geddes, John R., Sally Burgess, Keith Hawton, Kay Jamison, and Guy M. Goodwin. “Long-Term Lithium Therapy for Bipolar Disorder: Systematic Review and Meta-Analysis of Randomized Controlled Trials.” American Journal of Psychiatry 161, no. 2 (February 1, 2004): 217–22. doi:10.1176/appi.ajp.161.2.217.

Moncrieff, Joanna. Lithium and suicide: what does the evidence show? (JoannaMoncrieff.com. July 27, 2015)

According to its drug label, Depakote has been linked to emotional upset, psychotic-like experiences, aggression, psychomotor hyperactivity, hostility, disturbance in attention, learning disruption, and behavioral deterioration.

Related reading:

Cavanna, Andrea Eugenio, Fizzah Ali, Hugh Edward Rickards, and Dougall McCorry. “Behavioral and Cognitive Effects of Anti-Epileptic Drugs.” Discovery Medicine 9, no. 35 (February 20, 2010): 138–44.

According to its drug label, there are a number of ways in which Lamictal can be fatal at normal dosages:

• Lamictal can cause rashes which can become life-threatening and may not go away even after stopping taking the drug. According to its drug label, in some trials rashes requiring hospitalization occurred in about 1 in 200 children and adolescents, with slightly lower rates in adults. The rashes occur more frequently in the first weeks of treatment, but they can occur at any time for unknown reasons.
• Lamictal can also cause multiple organs in the body to fail simultaneously, which can lead to death. In some short clinical trials organ failures occurred in about 1 in 2,000 adults and 1 in 600 children.
• The drug has also been linked to neuroleptic malignant syndrome, a severe neurological disorder that can lead to death.

According to its drug label, there are a number of ways in which Depakote can be fatal at normal dosages:

• Depakote can cause acute liver failure and death, and the risk is highest for children under two years of age. (According to some studies, over half of people taking Depakote have abnormal hepatic enzyme values. Depakote seems to cause fatal liver damage in about 1 in 600 very young children, and the risk decreases with increasing age.)
• Depakote can also cause life-threatening pancreatitis. This can occur at any time during treatment, and in some trials occurred in about 1 in 1,200 people.
• The drug can also cause hyperammonemic encephalopathy, a condition that is characterized by elevated levels of ammonia in the blood and brain, which can lead to severe neurological disorders and death.
• Depakote can cause thrombocytopenia, or reduced amounts of platelets in the blood, which can lead to excessive bleeding and other side effects, including death. Over a quarter of people who take Depakote will experience reductions in platelet counts, though for some of these people platelet levels can normalize again while still taking the drug.

Related reading:

Bryant, Alton E., and Fritz E. Dreifuss. “Valproic Acid Hepatic Fatalities. III. U.S. Experience since 1986.” Neurology 46, no. 2 (February 1, 1996): 465–69. doi:10.1212/WNL.46.2.465.

Hussein, Raghda R. S., Rasha H. Soliman, Ahmed M. Abdelhaleem Ali, Mona H. Tawfeik, and Mohamed E. A. Abdelrahim. “Effect of Antiepileptic Drugs on Liver Enzymes.” Beni-Suef University Journal of Basic and Applied Sciences 2, no. 1 (March 2013): 14–19. doi:10.1016/j.bjbas.2013.09.002.

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.

Lithium, Depakote and Lamictal are not considered to be addictive drugs. They do not induce “cravings” after a period of regular use. However, these drugs can cause physical dependence. This means that, over time, the body and brain adjust to the presence of the drugs, and people can experience a wide variety of drug withdrawal symptoms if they suddenly stop taking them. For this reason, the drug labels for Lamictal and Depakote specifically warn that the drugs should not be discontinued abruptly. As of 2017, the drug label for lithium does not specifically indicate that it necessarily causes dependence, but many users in the layperson withdrawal community have reported experiencing withdrawal symptoms upon stopping lithium abruptly and it is currently a subject of discussion in the scientific literature.

It is not fully understood how lithium, Depakote or Lamictal affect the body and brain, and so it is also not understood exactly how sudden discontinuation of these drugs can produce uncomfortable, painful or dangerous withdrawal symptoms after a period of regular use. However, it is known that these drugs disrupt and alter basic sodium channel activity and sodium transport operations in the human nervous system, and also disrupt and alter the functioning of the neurotransmitters glutamate, GABA (gamma-aminobutryic acid), norepinephrine and serotonin. (Neurotransmitters are the key chemical messengers in the brain and body’s internal communications and functional systems.) For example, some anticonvulsants, at least in part, enhance or increase the activities of the neurotransmitter GABA. GABA’s main role seems to be to “inhibit” or decrease the activities of cells and other neurotransmitters in the body and brain. Human and animal studies suggest that, over time, the body compensates for or adapts to the ongoing presence of the drug – the body seems to do this in part by reducing its sensitivity to GABA and heightening its sensitivity to other neurotransmitters. Consequently, if a person suddenly stops taking the drug after a period of regular use, the person could experience an equally sudden “hyperexcitability” or increase in biochemical and electrical activities throughout the central nervous system until sensitivity to GABA is naturally restored.

In other words, we could think of an anticonvulsant as a sort of “brake” on some neurotransmitter activities. Over a period of time, the body adjusts and compensates by pressing more and more on its own internal neurotransmitter “gas pedals”. Then, if the drug-induced braking action suddenly stops while the body’s own internal gas pedals are still pressing hard, what happens? 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, seizures are one of the most dangerous withdrawal symptoms that can occur when abruptly stopping anticonvulsants. Other common withdrawal symptoms of lithium and anticonvulsants include mild-to-severe headaches, flu-like symptoms, irritability, nausea, sweating, agitation, anxiety, mania, depression, emotional volatility and mood swings.

There are virtually no formal scientific studies into the safest methods or time frames for tapering off lithium or anticonvulsant drugs.

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.

ICI has been gathering the anecdotal reports and accumulated insights from laypeople who have experienced psychiatric drug withdrawal. If you or someone close to you is considering tapering, you may find it helpful to read 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 The Inner Compass Exchange people considering coming off psychiatric drugs can also connect with others who have experienced psychiatric drug withdrawal, are in withdrawal, or are considering withdrawal.