Editor’s Note: Over the next several months, Mad in America is publishing a serialized version of Peter Gøtzsche’s book, Critical Psychiatry Textbook. In this blog, he discusses the harmful effects of lithium and anti-epileptic drugs used for bipolar disorder. Each Monday, a new section of the book is published, and all chapters are archived here.
Harms of lithium
Lithium is a highly toxic drug that requires tight monitoring of the serum level. The FDA warns that “lithium toxicity … can occur at doses close to therapeutic levels.”437
This fact was ignored in a textbook which claimed that lithium is generally well-tolerated, and that its harms are few and well known.18:115 It that were true, it is surprising that 40% of the patients interrupt the treatment prematurely, which the book mentioned on the same page.18:115
Another textbook respected the evidence. It mentioned that the most common adverse effects are polydipsia, polyuria, weight increase, hand tremor, gastrointestinal symptoms such as nausea, dyspepsia, and diarrhoea, minor oedema, and skin reactions, and that mental harms include difficulty concentrating, affected memory, and decreased vitality and creativity.17:662 The book noted that long-term harms are more serious: up to 10% of the patients have morphological changes in their kidneys, 1% have irreversible kidney damage, and hypothyroidism and teratogenicity occur in rare cases.17:662 A third textbook confirmed the risk of malformations.16:301
In package inserts, patients and their families are warned that the patient must discontinue lithium therapy and contact the doctor if they experience diarrhoea, vomiting, tremor, mild ataxia (not explained even though few patients know that it means loss of control over bodily movements), drowsiness, or muscular weakness. The risk of lithium toxicity is increased in patients with renal or cardiovascular disease, severe debilitation or dehydration, or sodium depletion, and for patients receiving medications that may affect kidney function, e.g. some antihypertensives, diuretics, and pain-relieving arthritis drugs. Very many drugs can change serum levels of lithium, which is therefore very difficult to use safely.437
There are other serious harms, e.g. lithium may cause cardiac conduction disturbances.16:299
One book claimed that cessation of lithium therapy increases the risk of a new manic episode beyond the risk associated with the natural course of the disease before lithium therapy.16:589 There was no reference to this statement, and—as for other psychiatric drugs—it is likely that what is seen when stopping lithium are withdrawal effects rather than relapse. The only relevant reference in this section was not about lithium but a network meta-analysis of psychosis pills in patients with schizophrenia.218
Lithium is similar to psychosis pills in its effects, which include emotional blunting, apathy, a decline in cognitive functioning, and impoverished lives with little social contact.5,135 Patients who come off lithium may end up worse than ever before,3 and the time to a recurrence following lithium withdrawal is several times shorter than it is naturally.427
Just like depression and schizophrenia, bipolar disorder appears to take a more chronic course now because of the drugs being used. In the past, about one-third of manic patients suffered three or more episodes in their lives, but now it is two-thirds, and depression pills and ADHD drugs may cause rapid cycling between ups and downs.5
The list of serious harms lithium can cause is very long and frightening,437 and we don’t know if the brain damage is reversible.11:204 This is not a drug I would recommend to anyone.
Psychosis pills, antiepileptics, and ECT
The textbooks recommended that, instead of lithium, one might use atypical psychosis pills or antiepileptics.16:297,18:241,19:220 One textbook did not recommend lithium as first choice for mania, instead recommending psychosis pills, which could be combined with benzodiazepines to avoid high doses.18:114 I doubt there is any good reason not to use benzodiazepines alone as the idea of treating mania is to calm the patient down, which is a question of dose.
This book noted that patients with mania and depression can usually be treated effectively with “modern” psychotropic drugs, which were claimed to prevent relapse in most patients, but there was no reference for this statement,18:110 which is false.438 Further on, it was specified that “modern” drugs meant psychosis pills.18:116
As noted earlier, “modern” is an inappropriate term to use, as it suggests that newer drugs are better than old ones, which is rarely the case, and psychosis pills do not prevent anything apart from letting the patients live more normal and productive lives. This book also claimed that, on medication, most manic episodes were over in 6-8 weeks, whereas an untreated manic episode lasted from a few months (most often) to several years.18:115 Obviously, this claim was not derived from placebo-controlled trials.
One book noted that there is no evidence for using antiepileptics for treatment resistant depression.16:275 The same book stated that valproate has a well-documented antimanic effect and that lamotrigine is approved for prophylaxis.16:302 It is not surprising that doctors think antiepileptics work for mania, as everything that knocks people down “works” for mania. The main effect of antiepileptics is that they suppress emotional responsiveness by numbing and sedating people.135
Like most other psychiatric drugs, antiepileptics are used for virtually everything. I have seen many patients entering the door of psychiatry with a variety of starting diagnoses—very often depression or nothing at all that qualifies for drug treatment—all ending up being prescribed a gruesome cocktail of drugs that include antiepileptics. Antiepileptics not only sedate people, they can also make them manic390,439 and thereby give the patients a false diagnosis of bipolar.
The trial literature has been distorted to an extreme degree. For gabapentin (Neurontin), for example, there was selective reporting of trials and of statistical analyses and outcomes that happened to be positive; patients were inappropriately excluded or included in the analyses; and spin made negative results appear positive.440,441
Bias was already introduced at the design stage, e.g. by using high doses that led to unblinding, although Pfizer recognised that unblinding due to adverse events could corrupt the study’s validity. The final layer of corruption was accomplished by ghostwriters and company bosses: “We would need to have ‘editorial’ control”; “The results, if positive, will … be published”; “We are using a medical agency to put the paper together which we will show to Dr. Reckless. We are not allowing him to write it up himself.”
Gabapentin was only approved for people with treatment-resistant epilepsy, but Warner-Lambert, later bought by Pfizer, promoted it illegally and sold it for virtually everything, including ADHD and bipolar disorder.6:151 Almost 90% of influential thought leaders were willing to tout gabapentin at meetings after having been updated on the company’s promotional strategies. A company executive told a salesperson about “Neurontin for everything … I don’t want to hear that safety crap.”442 The company insisted on pressing doctors to use much higher doses of Neurontin than those approved, which means more deaths.
In 2010, a jury found Pfizer guilty of organised crime and a racketeering conspiracy.443 Six years earlier, Pfizer had paid $430 million to settle charges that it fraudulently promoted Neurontin for unapproved uses.444
We have seen similar problems with other drugs. For lamotrigine, seven large, negative trials remained unpublished and invisible for the public, whereas two positive trials were published.7:193
Drugs for epilepsy have many harmful effects, e.g. 1 in 14 patients on gabapentin develops ataxia.439
One textbook claimed that some antiepileptics can be used for prophylaxis of bipolar.18:242 There were no references, but systematic reviews do not seem to provide support to this claim.445,446 I did not find it worthwhile to go any further, as the trials in this area are of such poor quality that it is a major undertaking to do a systematic review of each agent, and there are many antiepileptic drugs. Furthermore, antiepileptics are so toxic that I doubt their usage can be justified.
One textbook described several harms with antiepileptics,17:663 but not the most important one, which is that these drugs double the suicide risk. FDA’s package insert for pregabalin (marketed with great success by Pfizer under the seducing name Lyrica) mentions a meta-analysis of 199 placebo-controlled clinical trials of 11 antiepileptics that showed an adjusted risk ratio of 1.8 (1.2 to 2.7) for suicidal thinking or behaviour.390
“Mood stabiliser” is a euphemism the psychiatrists never defined. They usually mean antiepileptic drugs and lithium. Eli Lilly also calls olanzapine a mood stabiliser,7 which is Orwellian newspeak. Psychosis pills don’t stabilise anything, but sedate people, render them passive, and make it more difficult for them to live normal lives. This term should be abandoned, as it is intensely misleading.
This textbook admitted 345 pages later that there is sparse evidence for an effect of anti-epileptics, but that they are nonetheless used to some extent.16:577
I would not recommend antiepileptic drugs for any mental disorder.
A book claimed that ECT is the only monotherapy that is effective in over 60% of the patients.16:302 Another book went even further and said that 80% of patients with treatment-resistant depression responded to ECT,17:360 which is a meaningless statement, as there is no control group.
One book claimed that there is great potential in preventing more depressions and manias by offering a combination of drugs and psychoeducation as soon as the diagnosis of bipolar has been made.16:307 There is no reliable evidence that drugs can prevent relapse.
To see the list of all references cited, click here.
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