On Some So-Called Toxic Effects of Psychiatric Medications

AFFIRMING PSYCHIATRY

All medicines have potential toxic effects. Even over-the-counter medications such as hydroxyzine (Benadryl) can cause delirium, while ibuprofen can cause kidney failure and dextromethorphan can cause psychosis. Psychiatric medications have potential toxic effects as well. But in psychiatry, stigma leads to extra scrutiny and to the assumption that our medicines are illegitimate. Critics are not shy about proclaiming this belief to the world, with top-selling books such as Toxic Psychiatry and Anatomy of an Epidemic “showing” that psychiatric medications cause more harm than good. And today, our medicines are under more scrutiny than ever, with selective serotonin reuptake inhibitors (SSRIs) and stimulants on the short list for government censure.

Negative claims about psychiatric medications tend to morph over time. As research gets around to dealing with one negative assumption, others rear their heads. The game of whack-a-mole is never-ending, meaning that old disproven ideas are liable to be swept under the rug. Critics of psychiatry do not tend to be discouraged by their premature and misleading conclusions. Nor do they apologize afterwards for mistaken accusations. So just for review, here are some of the bigger faux-scandals of the past quarter-century.

SSRIs and Suicide

In 2003, the US Food and Drug Administration (FDA) issued a series of advisory warnings about the risks of antidepressants and suicidality in children and adolescents,¹ culminating with a black box warning in 2004. The FDA indicated that antidepressants “increased the risk compared to placebo of suicidal thinking and behavior (suicidality).” The effects of the warning were substantial: Antidepressant prescribing among this group decreased by 20% to 30%, while primary care physicians became less likely to even diagnose depression in youth.² At the same time, the youth suicide rate jumped by 15%, reversing a 10-year decline that preceded that year.³

In some ways, the excitement was justified—suicidality in this age group is dangerous and difficult to predict, and clinicians do need to be vigilant during the early phases of treatment. On the other hand, the FDA based its warning on clinical trials which showed an increase of suicidal ideation from 2% to 4% over placebo, and the data did not include a single actual suicide. The subsequent drop in antidepressant prescriptions did not lead to an increase in psychotherapy for youth suicide, as some had hoped.⁴ So it is likely that the warning led to some good results, and even more bad ones.⁵

Nevertheless, the debate over this issue has never been settled. Competing meta-analyses, re-analyses, and study designs have shown a spectrum of results, with hotly contested opinion pieces⁶ and at least one “re-analysis of the re-analysis” in print.⁷ Overall, it appears likely that antidepressants do reduce suicidality in young individuals (and other age groups) over the long term, but that a subset of youth may experience significantly increased suicidality when going on or off antidepressants.⁸ My point is not to suggest that there are no risks to antidepressants for youth. Rather, my point is that the heated overreaction to the FDA’s warning was due to the irrational underlying fear that any commonly used psychiatric medication is likely to somehow be toxic, not to the strength of the signal in the data, which remains relatively weak at best.

Benzodiazepines and Dementia

Early in this century, studies began to appear which suggested benzodiazepine use to be a risk factor for Alzheimer dementia.⁹ By the mid-2010s, the idea and the research behind it were picking up momentum,¹⁰ and the risk was being cited in The New York Times.¹¹ It is still being repeated in the pages of the Wall Street Journal.¹²

While it remains true that benzodiazepines can have negative cognitive effects, larger and more sophisticated studies have shown that benzodiazepines cause little, if any, risk of dementia.¹³ The problem with earlier studies (as with most studies creating controversies about psychiatric medications) is confounding by indication: The individuals who need to take the medicine are already at higher risk for the diseases in question. In the case of dementia, those who are prescribed benzodiazepines happen to have higher rates of diabetes, heart disease, depression, and anxiety. When researchers account for the effects of these on the risk of dementia, any contribution from benzodiazepines appears to recede.¹⁴ Thus, authors who confidently declare that benzodiazepine treatment is not “worth losing our minds over” because it gives us dementia, need to stop cherry-picking the evidence and check their own minds for stigma.¹⁵

Stimulants and Addiction

In the 1990s and early 2000s, increasing use of stimulants for attention-deficit/hyperactivity disorder (ADHD) raised the understandable fear that children who took them might be primed for adult substance use disorders. In 2008, National Institute of Drug Abuse Head Nora Volkow called this “one of the most controversial issues in childhood psychiatry….”¹⁶ Critics labeled stimulants “kiddy cocaine,” and as psychiatry critic David Healy, FRCPsych, put it, “The drugs used to treat ADHD are the same as speed and cocaine. We react with horror to the idea that our kids would use such drugs, but don’t react about drugs such as Ritalin being given them.”¹⁷

Countless studies and many meta-analyses later, the verdict was clear: Stimulant treatment in childhood does not increase the risk of substance use disorders later in life. Recent meta-analyses have found that childhood treatment has no effect at all on adult substance abuse,¹⁸ while large, population level studies have suggested that longer durations of treatment with stimulants actually decrease later rates of substance abuse.¹⁹ Regardless, widespread use of stimulants for ADHD has not created a generation of addicts, nor have stimulants turned out to act “the same ways as cocaine.”²⁰

Antipsychotics and Gray Matter

In 2005, researchers at the University of Pittsburg found that chronic treatment with antipsychotics reduced the volume and weight of macaque monkey brains by 8% to 11%.²¹ Although a human study by Lieberman et al the same year showed this effect only with haloperidol and not with olanzepine,²² journalistic stories such as “Antipsychotic Deflates the Brain”²³ soon followed. A later 2011 publication by B.C. Ho, Nancy Andreasen, and others²⁴ “dropped a bombshell” on the situation (at least according to antipsychiatrist Robert Whitaker writing in Psychology Today).²⁵ Ho and Andreasen found brain tissue loss correlating to the intensity of antipsychotic treatment, and accusations that psychiatrists were “blaming the illness” of schizophrenia for brain damage from antipsychotics increased in volume.²⁶ Though the controversy has never truly exploded into public consciousness, it has continued at a low buzz since then, and it is a regular staple of antipsychiatry publications. “We know that antipsychotics shrink the brain in a dose-dependent manner,” wrote Peter Gøtzsche, adding for good measure that “benzodiazepines, antidepressants, and ADHD drugs also seem to cause permanent brain damage.”²⁷

As it turned out, the issue has been more complex and difficult to decipher than anyone could have predicted. This is due to the fact that many other factors besides antipsychotic use can also cause brain tissue loss, including genetics, substance use, social isolation, physical inactivity, medication nonadherence, and relapse. In the case of schizophrenia, the disease itself is a well-established cause of brain loss, much of it occurring around the onset of symptoms.²⁸

As far as antipsychotic medications are concerned, animal studies with monkeys are not as strong as they first appear. Human brain loss with schizophrenia and/or antipsychotics amounts to 1% to 3% overall, in contrast to approximately 10% in monkeys taking antipsychotics. Just as importantly, there is little correspondence to the patterns of brain loss between monkeys in these studies and the humans with schizophrenia who take antipsychotic medications.²⁹ In regard to human studies, the results are highly uncertain because it is impossible to truly separate severity of illness (as well as treatment nonadherence) from the doses of prescribed antipsychotics: Those with more severe symptoms or frequent relapses are overwhelmingly likely to be on higher doses of medication. The only solution to this study limitation is to conduct prospective, randomized trials for new-onset schizophrenia with antipsychotic and placebo arms. Due to the technical and ethical challenges of such studies, only a few have been performed, and careful review of these studies does not show evidence of associated brain loss.²⁸

As with SSRIs and teen suicidality, I am not denying that an important and unresolved issue exists. As a prescribing psychiatrist myself, I am in genuine need of clarity about this issue based on further research. But even if antipsychotic medications do contribute to brain tissue loss, they would currently account for only about 10% of long-term tissue loss with schizophrenia, probably less than other factors such as substance use and inactivity.³⁰ Medication nonadherence and partial-adherence (difficult to measure in such long-term studies) may also account for brain tissue loss in human studies.³¹ All of this is a far cry from what articles such as, “Neuroleptics do much more harm than good and should not be used”³² would imply. So instead of further confusing and demoralizing patients and families about this issue, maybe critics should join us in seeking increased funding for comprehensive and humane treatment for psychotic disorders, treatment which includes both medicines and psychosocial supports.

SSRIs and Birth Defects

This controversy is still going strong, but dates back to the early 2000s. In December 2005, the FDA issued a health advisory which alerted the public that the SSRI paroxetine could increase the risk of malformations, particularly cardiac malformations.³³ This was based on 2 not yet published studies, one from a Swedish national registry and one from an insurance database. The studies showed an increase of such malformations from 1% to 1.5% to 2%.³⁴ Under the direction of the FDA, paroxetine’s pregnancy category was downgraded from C to D. The FDA admitted that the 2 studies conflicted with other information regarding the safety of paroxetine in pregnancy, but decided to err on the side of warning the public.

Just 1 year later, the FDA issued another warning, this time for all SSRIs.³⁵ Based on the evidence of a single study, the FDA warned that maternal SSRI use after 20 weeks of pregnancy was associated with persistent pulmonary hypertension in newborns (PPHN), a serious and potentially fatal condition. But in 2011, the FDA revised its warning based on further studies: “Given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN.”³⁶

Even more further studies have not fully clarified the risks of major malformations and PPHN with SSRIs, although it is now evident that any contribution of SSRIs to these conditions is quite small. However, 2 things have become clear: First, depression itself appears more likely to harm mothers and infants than SSRI antidepressants. Maternal depression is a risk factor for major malformations, preterm birth, and low birth weight, in addition to higher rates of gestational diabetes, preeclampsia, and C-section.³⁷ Second, most studies have had trouble fully accounting for this fact, such that studies which do provide control groups with psychiatric illness show little or no increased risk of these conditions. For instance, absolute rates of PPHN may increase slightly from 0.1% to 0.2% to 0.2% to 0.3% with SSRI use. Even with this in mind, experts agree that risks of SSRIs must be balanced against the risks of depression, and that the balance of probabilities usually favors SSRI use.³⁸

This is where the story ended, until just this year, when an FDA advisory panel met to reconsider the question. Under the leadership of the current HHS Secretary, the group’s membership now includes 9 of 10 members who have publicly disparaged SSRI use. Among the sage opinions voiced by these 9 worthies were the view that depression is not an illness, that fetal alcohol syndrome is 10 times more likely with SSRIs, and that treating mothers with depression does not benefit their babies. Afterwards, actual experts on maternal depression begged to differ with such self-proclaimed “efforts to apply rigorous, evidence-based standards to ingredient safety.”³⁹

Concluding Thoughts

All the above concerns are legitimate. All medicines have significant risks, and we want to know precisely what they are. Psychiatric medications are neither poisons nor magic pills. They are both as effective and as risky as other types of prescription medications. Doctors and patients should be wary of possible harmful effects. On the other hand, Americans happily consume 13 billion dollars’ worth of untested alternative medications every year.⁴⁰ Since we have minimal safety data on those over-the-counter substances, it would appear that as a nation we are far more fearful about some medicines than others. And we are most fearful about psychiatric medications. This fear has so much intensity that every emergence of a possible risk with a psychiatric medication is followed by a panicked stampede toward the conclusion that the worst is true. The reason for this is not rational caution. It is stigma: covert, powerful, and pervasive.

I would not want people to disregard the risks of our medications. Much of my professional time is spent weighing those risks with my patients. At the same time, our culture does not treat psychiatric medications like any other class of medication, whether prescription or over-the-counter. Our public treats psychiatric medications as if they were shameful vices, and our intelligentsia treats psychiatric medications as if they were radioactive. This does our patients no favors, making them even more likely to disregard prescribed treatments. As psychiatrists and mental health clinicians, it is our duty to respond to these fears and distorted ideas, and to the prejudicial views of mental illness that lie behind them.

The author would like to thank Ronald W. Pies, MD, for his helpful review of an earlier version of this article.

Dr Morehead is a psychiatrist and director of training for the general psychiatry residency at Tufts Medical Center in Boston. He frequently speaks as an advocate for mental health and is author of Science Over Stigma: Education and Advocacy for Mental Health, published by the American Psychiatric Association. He can be reached at [email protected].

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