Advertisements for SSRIs May Be Misleading

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Advertisements for SSRIs May Be Misleading 


Laurie Barclay, MD


Information from Industry
Advertisement – Medical comorbidity in schizophrenia:
Treating comorbidities has significant benefits in psychosocial functioning and quality of life.

Nov. 8, 2005 — Advertisements in the U.S. for selective serotonin reuptake inhibitors (SSRIs) are not based on science, according to an essay published in the December issue of the Public Library of Science (PLoS) Medicine. Since the 1960s, investigators have proposed the "serotonin hypothesis," which implicates low brain levels of serotonin in depression. However, extensive research to date has failed to confirm this theory.

In 1965, Joseph Schildkraut suggested that depression was linked to low levels of norepinephrine, but investigators subsequently proposed that serotonin was the responsible neurotransmitter. Numerous studies to identify reproducible changes in neurotransmitter levels in the cerebrospinal fluid of clinically depressed patients, or to induce or correct depression by manipulating brain serotonin levels, were inconclusive and fraught with methodological limitations. Contemporary research has failed to prove any serotonergic lesion in any mental disorder, according to the PLoS Medicine essay.

Consumer advertisements for SSRIs in the U.S. "typically claim that depression, or other psychiatric condition, is probably caused by a chemical imbalance of the neurotransmitter serotonin, and that SSRIs correct this imbalance," lead author Jeffrey R. Lacasse, MSW, a PhD candidate at Florida State University College of Social Work in Tallahassee, told Medscape. "They routinely use visual portrayals of a nerve synapse demonstrating the action of SSRIs, showing a 'chemical imbalance' which is then 'corrected' by the medication."

Gordon McCarter, PhD, an assistant professor of biological sciences at the College of Pharmacy of Touro University in Vallejo, California, agreed that the evidence for an "imbalance" in neurotransmitters causing depression is "circumstantial" and "more and more tenuous." He noted the dearth of studies showing any measurable difference in serotonin or norepinephrine between depressed patients and controls, with the limited positive findings based on suicide victims. Dr. McCarter was not involved in the PLoS Medicine essay.

"This doesn't mean there isn't a difference, [but] it may be too localized and too small to measure with current techniques," Dr. McCarter told Medscape. "Serotonin clearly plays a role in some [cases of] depression and blocking its reuptake clearly helps many depressed patients, but this may be a symptomatic approach. Current thinking is that genetics, perhaps regarding serotonin-handling molecules in some cases, combined with life history affects the likelihood that stressful life events will trigger a depressive episode. Stating that depression is caused by a chemical imbalance is extremely simplistic."

The evidence that is usually used to support the claim of a serotonin imbalance, according to Mr. Lacasse, is the efficacy of SSRIs. Because SSRIs have an effect on depression, and SSRIs affect serotonin, the conclusion touted in the ads is that depression is due to serotonin imbalance. However, this line of reasoning may be inherently flawed; aspirin may relieve headache, but we do not therefore conclude that headaches are caused by low levels of aspirin in the brain.

Another difficulty with using the efficacy of SSRIs in depression to bolster the serotonin hypothesis is that the efficacy itself is problematic. A meta-analysis cited in the PLoS Medicine essay reviewed all clinical trials of antidepressants submitted to the U.S. Food and Drug Administration (FDA). This meta-analysis showed that placebo duplicated about 80% of the antidepressant response, and that more than half of pharmaceutical company–sponsored trials failed to show a statistically significant difference between antidepressant and placebo. Moreover, antidepressants that do not affect serotonin are as effective as SSRIs in reducing symptoms of depression, and even placebo and nonpharmacologic treatments have been shown to have robust effects.

"The etiology of depression and anxiety is still a mystery, and this is reflected in the scientific literature," senior author Jonathan Leo, PhD, a professor of neuroanatomy at Lake Erie College of Osteopathic Medicine in Bradenton, Florida, told Medscape. "The Diagnostic and Statistical Manual of Mental Disorders does not list serotonin as a cause of any mental disorder; it is simply one neurotransmitter that continues to be investigated. And the prescribing information for the SSRIs does not claim that their mechanism of action is to correct a chemical imbalance, although this is exactly what the advertisements claim."

The PLoS Medicine essay cites a recent review article on depression published by John Mann in the New England Journal of Medicine, which lists a dozen chemicals potentially involved in depression, and several pharmacologic interventions that do not affect serotonin; and a Cochrane review showing no major difference in efficacy between SSRIs and tricyclic antidepressants. Bupropion and reboxetine, which do not significantly affect serotonin, were shown to be as effective as SSRIs in the treatment of depression. In recent randomized controlled trials, St. John's wort and placebo were each more effective for depression than SSRIs, and exercise was as effective as the SSRI sertraline.

"The pharmaceutical industry has managed to convey a misleading picture," Joanna Moncrieff, MD, a senior lecturer in psychiatry at University College London, U.K., told Medscape. "I speak to quite a few journalists, and they are shocked to hear that the link between serotonin and depression is very tenuous and the research conflicting and not convincing. The psychiatric profession and academic researchers are probably also partly to blame for glossing over the weakness of the research."

The FDA is charged with the duty of regulating direct-to-consumer advertising (DTCA), and with ensuring that it is grounded in scientific evidence. However, the PLoS Medicine essay points out the "remarkable, and possibly unparalleled" disconnect between the scientific literature and the SSRI ads.

"All prescription drug advertising is to be fair and balanced, with an accurate portrayal of the benefits versus the risks," FDA spokesperson Crystal Rice, from the Trade Media and Exhibits Center for Drug Evaluation and Research, told Medscape. "There would be no difference with regard to these drugs — as with any drug, these same rules apply. Concerning what information must be disclosed and in what manner, and how that would apply specifically to this situation, this is done on a case-by-case basis and dependent on the specific product and specific promotional piece."

The FDA requires that drug advertising present the most serious risks and the most common risks, according to Ms. Rice. The Division of Drug Marketing, Advertising, and Communications works closely with the medical review divisions and others in the FDA in determining which specific risks should be presented. The FDA has requested a labeling change for antidepressants, now requiring that drug companies include the warning about increased risk of suicidality in their advertising promotion. Until Feb. 28, 2006, the FDA has an open docket seeking the public's input on DTCA (http://www.fda.gov/OHRMS/DOCKETS/98fr/05-18040.htm).

"I don't really think [DTCA statements about serotonin in depression] are untrue, especially if they are presented with qualifiers such as 'research suggests' and 'scientists believe,' but they might be bordering a little on unbalanced, so I think the FDA could be doing a little better in this regard," Dr. McCarter said. "By implying that depression is 'only' a chemical imbalance, [the ads] are leaving out very important aspects of the depression story. A 'balanced' statement on the etiology and treatment of depression directed at consumers should note that certain forms of counseling or psychotherapy, in particular cognitive-behavioral therapy, is equally effective in the treatment of major depression as antidepressant medication, and that together they are even better."

The PLoS Medicine essay notes that SSRIs are now among the best-selling drugs in medical practice, thanks in large measure to successful advertising campaigns. The marketing emphasis in SSRI ads on a theoretical serotonin imbalance appears to be specific to the U.S., causing "striking differences" from advertising in the EU. Unlike the U.S., the EU does not allow DTCA.

"Two very different pictures emerge of the same exact medication, depending on government regulation and marketing practices," Dr. Leo said. "It's two very different political climates. We suspect that one important factor is the amount of influence that pharmaceutical companies hold in a particular society."

The British equivalent of the FDA, known as the Medicines and Healthcare products Regulatory Agency (MHRA), and U.K. medical literature published in the British Medical Journal and elsewhere have preceded the FDA in their open criticism of U.S. marketing practices for SSRIs.

"I personally feel that all drug advertising should be banned both to professionals and patients," said Dr. Moncrieff, who is also a founding member and cochair of the Critical Psychiatry Network. "Information about drugs should come from independent sources that people can access if required, and not be constantly shoved into people's faces. We currently have a manufactured epidemic of psychological disorders, and the drug industry is at least partly to blame."

However, Dr. Leo and Mr. Lacasse are not convinced that a ban on DTCA would eliminate misinformation about the serotonin theory.

"We suspect that this theory is repeated to patients by physicians, and that the problem is not limited to DTCA," they explain. "Depression and anxiety are complicated issues that cannot be explained in a 30-second commercial.... When the serotonin theory is portrayed with clever visual portrayals that do not accurately represent the neuroscience research, consumers are led to believe that medication is necessary for the treatment for depression."

Ostensibly absent from commercials is information concerning alternatives to medication, including evidence from randomized controlled trials that psychotherapy and exercise are effective in the treatment of depression; and significant adverse effects from SSRIs, including very high rates of sexual dysfunction. Other issues typically omitted from DTCA are difficulty in withdrawing from SSRIs in some patients; the self-limited nature of depression for many people, in whom it lasts for only several months; and the robust placebo effect documented in the overwhelming majority of clinical trials.

Dr. McCarter suggests that the FDA or even the National Institutes of Health might provide clear and concise information on the issues surrounding specific prescription drug classes, and treatments for diseases in general.

"Perhaps drug companies could be required, whenever they wish to advertise a prescription drug, to pay into a fund that provides public service announcements regarding that particular therapeutic area," he said. "Maybe there should be required a general 'balance statement,' produced by the FDA to accompany any advertising — short and sweet, not like the notorious 'brief summaries' that were fired out in staccato or squished into microscopic text on the next page."

Another important concern embedded in DTCA is the issue of informed consent, which Mr. Lacasse and Dr. Leo believe is essential to an ethical and productive physician-patient relationship.

"If a patient comes into the office believing the serotonin theory and the doctor doesn't take the time to correct them, we wonder where that leaves the issue of informed consent, and especially the issue of potential risks and benefits," they point out. "We suspect that many consumers believe the serotonin theory to be more scientifically based than it is, and that they might have chosen an alternative approach to their distress if they were fully informed. These ads work to confound informed consent, essentially."

One example is a television ad for sertraline (Zoloft), which portrays a serotonin imbalance and claims, "Prescription Zoloft works to correct this imbalance." DTCA for fluoxetine (Prozac), Paxil, escitalopram (Lexapro), and other SSRIs has voiced comparable messages.

"In terms of real-life effects of this advertising, we are concerned that this oversimplified theory has become the intellectual justification for 10-minute office visits which result in the prescription of antidepressants for a variety of ill-defined conditions," Mr. Lacasse concluded. "In general, people need to be more skeptical regarding claims of chemical imbalance as explanation for psychological distress."

On the other hand, Dr McCarter believes that heightening consumer awareness of depression may produce some positive effects.

"While the 'chemical imbalance' message is overly simplistic and may mislead the audience away from an understanding of the cognitive and behavioral aspects of depression, if it gets someone who is suffering from this disease to think about seeing a doctor or even just to consider for the first time that there is a biological aspect to it, then some overall benefit has been achieved," he said. "I just wish there were other equally prominent information sources that were not produced under a profit motive."

Drs. Lacasse and Leo report no competing interests and no commercial funding for this work.

PLoS Med. 2005;2(12):e392

Reviewed by Gary D. Vogin, MD


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Serotonin toxicity, serotonin syndrome

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Introduction

There has been, and there remains, much misunderstanding and misinformation concerning serotonin toxicity, both in medical, and non-medical, texts. This includes prestigious medical journals and books that are usually revered as authoritative and accurate.
Important original research has been published during 2003 and 2004 (especially Professor Whyte’s HATS data) that makes much of what has previously been written redundant (1-15).
Serotonin toxicity only occurs after the ingestion of drugs that increase brain serotonin levels. There is no other disease or a natural cause for this constellation of symptoms and signs. It is poisoning caused by serotonergic agents. The typical side effects caused by usual therapeutic doses of the SSRIs, which are the most widely known and used serotonergic drugs, increase with increasing dose. There is variation between individuals in the susceptibility to various typical side effects and also the actual blood level (and therefore ‘end-effect’) goes up more rapidly with some drugs than with others as the dose is increased. This is because some drugs (like fluoxetine and paroxetine) have ‘non linear’ pharmacokinetics. Side effects may include the agitation and increased suicidal propensity that is possibly experienced by some individuals and about which there has been much written lately. Another example is the quite marked muscular jerks that happen during sleep, they probably represent myoclonic phenomena which are usually considered as diagnostic of ST. (*the term side effects in this context is something of a misnomer because the effects being referred to are an inevitable consequence of the drugs main intended mechanism of action, i.e. reuptake inhibition of serotonin, resulting in increased serotonin levels. These inevitably cause, for instance, tremor, diarrhoea, retarded orgasm etc. Whether retarded orgasm is regarded as a side-effect or a benefit depends on what effect you wanted.)

These idiosyncratic responses do not alter the evidence that the general pattern of side effects gradually become worse with increasing ‘dose’, and reach a degree of severity which justifies calling them toxic effects, in a dose-related manner (16). The meaning of the word toxicity is ‘poisoning’, and that insinuates life threatening consequences. If we are being precise the term ST should be reserved for those cases sufficiently severe to require hospital admission and medical intervention. It is appropriate to remember that all of us tend to be careless in the use of words and terms, but nevertheless this distinction, if born in mind, will help to maintain clarity of thinking. There will sometimes be dispute about whether a given clinical case is most appropriately described as ‘severe’ or ‘atypical’ side effects, or as ‘toxic’ effects. Probably the most relevant and objective criteria is body temperature.

That is the change that mediates the severe life threatening effects of ST. A key goal of medical management is to predict those cases that may become sufficiently severe to necessitate active intervention. It is now beyond reasonable argument that the degree of serotonin toxicity exhibited in experimental animals, given combinations of drugs that elevate serotonin levels, gradually increases, eventually causing excessive body temperature (hyperpyrexia) and death as a result: this is a ‘dose-related’ phenomenon (15, 17, 18). When pharmacologists say ‘dose-related’ what they really mean it is related to the end effect of the drug. In human beings there are intervening variables relating to metabolism that cause large variations in the actual level of the drug at the sight of action. This means that the direct relationship between dose and effect is less precise than it is in inbred laboratory animals. Serotonin toxicity illustrates this point further, because there are cumulative effects caused by the end effect of two different drugs producing an additive effect which is much larger than either individual drug is able to produce by itself. For these reasons the term ‘dose-effect’ relationship needs to be understood as the cumulative effect of all drugs taken on the relevant measure, which in this case is the intra-synaptic serotonin level.

It is also now clearly established that drugs that block 5-HT2A post-synaptic receptors prevent deaths from hyperpyrexia in animals and very probably do the same in Humans (3, 5, 10, 14, 15, 17, 19, 20). Contrary to much published comment, 5-HT1A receptor antagonists (blockers) make serotonin toxicity worse, not better (21). This leads to the inescapable conclusion that the most important consequences of serotonin toxicity are mediated by 2A receptors. If this were more widely known and appreciated some of the recently reported deaths and serious cases may have been avoided (22-25).
The more recent papers mentioned above, particularly those from Professor Whyte’s HATS research group, have now clearly established the typical clinical picture, the diagnostic features, and also validated clear diagnostic decision rules for serotonin toxicity (13).

One of the main reasons for using the term serotonin toxicity rather than serotonin syndrome is because this emphasizes that it is a form of poisoning, not an idiosyncratic syndrome: i.e. a syndrome usually implies something that occurs in some people, but not in others. Neuroleptic malignant syndrome is idiosyncratic and rarely occurs after over-dose of neuroleptics: rather it occurs in a very small proportion of patients who are taking average, or above average, therapeutic doses (4, 26). NMS is quite different to ST (26-29).
The usefulness of conceptualising the problem as serotonin toxicity, rather than serotonin syndrome, is made evident in a variety of ways. For instance, consider the frequent comment ‘serotonin syndrome is rare….’ and then the statement ‘poisoning is rare’; it is true that poisoning is rare, except in those who ingest poisons. However, neither statement is much more helpful or revealing than saying “it never rains if the sky is blue”.

This point is consonant with Bayesian theory: this states that the probability of an ‘experiment’ cannot be properly calculated without factoring in our estimate of the prior probability (30). So if you feel something like rain falling on you when the sky is clear and blue ‘natural common sense’ (a form of Bayesian reasoning) tells you it may be your neighbour with an over exuberant garden sprinkler, rather than a miracle (31, 32). This important logical principle was popularised more recently by the astronomer Carl Sagan as …‘extraordinary claims require extraordinary evidence’ (33). This line of thought originates from the Scottish philosopher David Hume (1711-1776) who launched an effective critique of miraculous claims (34). This sceptical rationalism was a major challenge to religious belief throughout the later 18th and 19th centuries. Those who enjoy a good chortle might care to read the splendid essay by Darwin’s cousin, Francis Galton, funded by Wedgewood potteries, on the effect of prayers on missionary ships vs. merchant ships: see http://galton.org/essays/1870-1879/galton-1872-fortnightly-review-efficacy-prayer.html

It is difficult to suffer from poisoning if you haven’t taken a poison. This is a slightly trite way of expressing the idea that the most important piece of information for doctors to know if they are dealing with a possible case of serotonin toxicity is: what drugs have been ingested? The ingested drugs determine the form of poisoning and large enough doses will produce poisoning in all people, even if there is some inter-individual variation in susceptibility. This is what has led to the first diagnostic decision rule from the HATS data which is: a definite prediction of impending serotonin toxicity can be confidently made if a known potently serotonergic drug has been ingested and the single physical sign of clonus is present (13). Similarly one can state that if a mixture of MAOIs and SSRIs has been ingested there is (at least) a 50 per cent probability of life threatening serotonin toxicity (6, 12): even if the patient currently appears well they must be observed in an intensive care unit (35).

In order to understand the more subtle complexities of this issue it is necessary first to remember that serotonin toxicity is mediated by an increase in the level of serotonin in synapses in the central nervous system*, which then excessively stimulate all types of post synaptic serotonin receptors. Because there are several types of drug with different mechanisms of action, each of which can increase serotonin levels to differing degrees, there is a characteristic degree of severity associated with each type of drug when taken by itself, either in normal therapeutic doses, or in over-dose. For instance, over-doses of selective serotonin reuptake inhibitors (SSRIs)-alone do not produce dangerous toxicity or temperatures in excess of 38.5c (5); however, an overdose of an MAOI like tranylcypromine-alone will produce hyperpyrexia, and even death (2), but over-dose of the RIMA moclobemide-alone does nothing. This demonstrates that the maximum elevation of serotonin produced by these mechanisms is significantly different, being greater with the old irreversible MAOIs.

*Because serotonin is unable to cross the blood brain barrier conditions such as carcinoid syndrome that involve considerable increases in peripheral serotonin cannot cause CNS symptoms.
The bodies capacity to break down serotonin is so rapid that it seems to be difficult to raise levels sufficiently high to cause death (from serotonin toxicity) by taking only one type of drug (e.g. MDMA, ecstasy (3,4-methylenedioxymethamphetamine)). It is almost always the case that serious toxicity and death is associated with combining two different types of drug with a different mechanisms of action. A great majority of human fatalities are associated with a combination of MAOIs and (S)SRIs. So far, just about the only other combination capable of causing fatalities is MAOIs with serotonin releasers (‘indirect agonists’) e.g. Amphetamine (but not methylphenidate) and MDMA.

Over-Doses of SSRIs-alone cause a marked increase in serotonergic side effects which, in about 15 per cent of typical over-dose cases, leads to a degree of symptoms sufficiently severe to cross an arbitrary threshold of severity which has been commonly referred to as ‘serotonin syndrome’. However, as argued above, the term serotonin syndrome is unhelpful and it is more helpful to understand that there is a gradually increasing degree of severity of serotonergic effects, which at some point on the severity spectrum, it is appropriate to call ‘toxicity’.

One important reason for trying to understand all this is because some patients die. The question is, can we predict which patients are likely to die without treatment?

The answer is unequivocally yes, as a result of the information and concepts above. We now know that even very large over-doses of SSRIs rarely or never cause life threatening serotonin toxicity (5). The dramatic illustration of the usefulness of the ‘dose-effect’ idea (the spectrum concept) is that about 50 per cent of patients who take an overdose of a mixture of MAOIs (of the RIMA sub-type) and SSRIs experience serious serotonin toxicity which is life threatening, and often requires treatment with 5-HT2A antagonists (12) (the old MAOIs + SSRIs are even more likely to precipitate severe ST).

The only other combination that can produce life threatening toxicity is that of an MAOI and a serotonin releaser. This means a combination of moclobemide (or older MAOIs like tranylcypromine) with either Amphetamine or MDMA. Such combinations are almost exclusively a result of the illicit drugs scene, although they could occur if a doctor used amphetamine and moclobemide or tranylcypromine etc together (see table).

Fatalities do occur with larger single drug over-doses of the old irreversible MAOIs, such as tranylcypromine. There is some uncertainty about whether this is from purely serotonergic effects, or from other effects (i.e. dopamine and noradrenaline). This is in dramatic contrast the newer RIMA moclobemide which does not even cause significant serotonergic side effects when taken in over-dose by itself, never mind serious serotonin toxicity (12). This illustrates the large difference in the effect on brain serotonin levels of these two types of drug. In my opinion, this may also explain the substantial difference in their effectiveness for the treatment of depression (tranylcypromine good, moclobemide poor).
ST has now been more clearly characterized as a triad of neuro-excitatory features.
Neuromuscular hyperactivity; tremor, clonus, myoclonus, hyperreflexia, and (in the advanced stage) pyramidal rigidity.

Autonomic hyperactivity; diaphoresis, fever, tachycardia and tachypnoea.
Altered mental status; agitation, excitement and (in the advanced stage) confusion.
Professor Whyte’s group have applied decision tree rules (CART) to their large data set and shown that only the symptoms of clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia are needed for accurate diagnosis of serotonin toxicity. Their diagnostic rules are in their paper, which should be consulted (13). They demonstrate that if, in the presence of a serotonergic drug (see table for what is a clinically significant serotonergic drug), spontaneous clonus is present ST may be reliably diagnosed.

Clinically, the onset of toxicity is usually rapid, because it results from drug combinations and starts when the second drug reaches effective blood levels. The clinical picture is often alarming, and rapidly progressive after the first or second dose of the second serotonergic drug in the patient’s regime. The patient is often alert, with tremor and hyperreflexia. Ankle clonus and myoclonus are usually demonstrable. Neuromuscular signs are initially greater in the lower limbs, then become more generalized as toxicity increases. Patients may exhibit pronounced tremors. Other symptoms may include shaking, shivering often including chattering of the teeth and sometimes trismus. Pyramidal rigidity is a late development in severe cases, and when it affects truncal muscles that impairs respiration. Rigidity, decreasing PaCO2, and a fever of >38.5ºC heralds life-threatening toxicity.

The above information indicates that one of the most important things is to have an accurate list of drugs with significant clinical potency on the serotonin system in humans. A brief table of the important drugs is below, but the detailed justification of why particular drugs are included or excluded requires much more extensive and detailed study of other references.

Some of this information is covered the references below: it is comprehensively reviewed in my research document, updated yearly (35,000 words, 600+ references) - Serotonin toxicity, serotonin syndrome: 2006 update, overview and analysis.
NB This document is usually only made available to bona fide researchers in the field.

Drugs with clinically relevant serotonergic potency
From reference:--(36, 37)
Serotonin reuptake inhibitors (selective and non-selective)
Paroxetine sertraline fluoxetine fluvoxamine citalopram.
venlafaxine milnacipran duloxetine sibutramine.
clomipramine imipramine (but not other TCAs).
tramadol pethidine fentanil (and congeners) methadone dextromethorphan dextropropoxyphene pentazocine (but not other opioids).
chlorpheniramine brompheniramine (but not other anti-histamines).
Serotonin releasers
Amphetamine MDMA.
Monoamine oxidase inhibitors
Tranylcypromine phenelzine nialamid iproniazid isocarboxazid.
pargyline selegiline clorgyline.
moclobemide toloxatone.
furazolidone procarbazine linezolid.
Methylene Blue

Table notes

Although clomipramine and imipramine do precipitate ST, none of the other TCAs are able to because they are too weak as SRIs. Trazodone, nefazodone, mianserin, mirtazapine are neither SRIs nor significantly serotonergic. Also, they do not precipitate serotonin toxicity with MAOIs see (21).
Fatalities from ST involving opioids have been with pethidine, tramadol and dextromethorphan and, possibly fentanil. See (21).

Methylphenidate appears insufficiently potent as a serotonin releaser to precipitate serotonin toxicity.
Despite one or two odd reports tryptans do not appear to be associated with ST.
For the Methylene Blue story see (38