Long-term treatment with antipsychotic medication apparently causes a decrease in brain volume, according to a new report by Nancy Andreasen’s group at the University of Iowa in this month’s Archives of General Psychiatry. In the study, over 200 schizophrenic patients, treated with antipsychotics, underwent MRI scans of their brains at various intervals over a 5-14 year period. The results showed that the “intensity” of antipsychotic treatment (i.e., doses and lengths of treatment) correlated with the reduction in brain tissue.
Instead of just looking at an overall “snapshot” of the brain, researchers calculated the volumes of several brain regions (from the whole-brain MRI scans) and found, on average, subtle decreases in both gray matter and white matter volumes, as well as enlargement of the ventricles (the “spaces” in the normal brain). The changes were more pronounced with longer time periods of treatment and, in particular, when higher doses of antipsychotics were used for extended periods of time.
As expected, this finding has generated a great deal of interest— if not concern– and more than a touch of “I-told-you-so” from certain camps (see “Antipsychotics Shrink the Brain” by Robert Whitaker). Indeed, at first blush, it is quite shocking to think that the first-line treatment for such a devastating brain disease might cause damage to the very organ we are trying to treat.
But is it really “damage”? All joking aside, I think the title of this post needs to be taken seriously. Does the observed loss in brain tissue loss mean that a person is incapacitated in any way? That he can no longer think, feel, see, taste, or make plans for the future? Moreover, despite the headlines, the tissue loss was not incredibly dramatic. In other words, we’re not talking about a healthy, robust brain turning into a moth-eaten mass of Swiss cheese. In fact, by my read of the data, the largest individual change in frontal gray matter volume was from about 330 cm3 to 290 cm3 over a 10-year period (yes, that’s >10%, but who knows what else was happening in that patient?). Other changes were much smaller, and many patients actually showed increases in brain volumes.
There were slight correlations with disease severity (more symptomatic disease was associated with a greater decrease in brain volume), and different classes of antipsychotics affected some regions of the brain differently than others. Interestingly, there seemed to be no independent effect of substance abuse on brain volume changes, despite the oft-heard warning that drugs and alcohol “kill brain cells.”
So what does this all mean? Obviously, some will say that this provides evidence that antipsychotics are toxic to brain cells. But there’s no clear evidence that neurons are actually dying; in some studies in monkeys taking antipsychotic medication, the number of neurons remains constant, but they increase in density because support cells (called glia) decrease in number– resulting in the macroscopic appearance of a “smaller brain.”
Moreover, it is quite possible that the disease process itself already leads to a decrease in brain volume (actually, we know this already) and effective treatment helps to further “prune” dysfunctional areas of the brain. In fact, an editorial accompanying the article claims that “strategic reductions in brain volume” might actually be therapeutic, and reminds us that gray matter volume decreases significantly during human adolescence, a process thought to underlie the organization and refinement of brain cells, and elimination of redundancy. (No wonder you have to tell your teenage son six times to clean his room.)
The best way to tackle this question, of course, is to take two groups of schizophrenics, treat one “as usual” with antipsychotics and the other with no medication at all, and perform brain scans at regular intervals. For ethical reasons, we can’t do this (it’s unethical not to treat a psychotic patient with an antipsychotic– although some would argue differently). Another way is to take advantage of the fact that many non-schizophrenic patients are now taking antipsychotics for OTHER diagnoses– bipolar disorder, depression, anxiety, insomnia, PTSD (just to name a few)– and we could compare those on antipsychotics to those on other drugs. If we see brain tissue loss across a wide spectrum of diagnoses, it suggests that this effect may be a direct result of antipsychotic treatment, even though the mechanism remains unknown.
Regardless of what’s actually happening in the brains of treated schizophrenics– and whether it’s “good” or “bad,” or whether it resembles the brain loss observed in birds living near Chernobyl— two things must be kept in mind. First, the patient’s well-being is of utmost importance; it would be inappropriate to withhold antipsychotic treatment from a patient who is clearly tormented and disabled from his paranoia, his delusional preoccupations, and his absolute lack of insight, particularly when we know that such medications do, in most cases, result in dramatic improvement. At the same time, we must also consider the other side of the coin, namely that if antipsychotics might cause an unexplained loss in brain tissue—or any other anatomic defect elsewhere, for that matter—we must seriously consider our rationale for these drugs. In particular, brain development in children is an ongoing process, not complete until late adolescence or early adulthood.
Hopefully this finding will stimulate research to determine how antipsychotics affect brain cells over time. Perhaps then we can find ways to preserve brain structure – or, at least, essential brain structure—while still treating the symptoms of mental illness. In other words, avoiding harm, while still doing good.
Thought Broadcast 
First, I have to say I’m concerned that a psychiatrist would refer to “glia” as “support cells” and imply that they are of minor significance compared to neurons. New research is showing that glial cells are crucial to the chemical processes involved in neurotransmission. This tends to reinforce my impression that there’s a dangerous disconnect between neuroscience and psychiatry today.
Second, I have to say that comparing the normal developmental “pruning” process of the adolescent brain to the loss of gray matter in adults undergoing a pathological process is inappropriate and misleading. It’s like saying that if a five-year-old developed pubic hair and adult genitalia we shouldn’t be concerned, because after all, teenagers do, right?
Third, I have to say that although the association of use of antipsychotics with this brain volume loss cannot be proven to be causal in humans, for the reasons you describe, there are strong indicators in animal studies that it is so, and it’s misleading not to make reference to this data.
Fourth, the fact that alcohol does not appear to cause brain loss is absolutely irrelevant. Neither does cheese, apparently. Once again, misleading and misdirecting argument.
However, thank you for admitting that the use of drugs that affect brain development and structure, in ways that have neither been well studied nor well characterized, in children with developing brains may not be the most brilliant idea psychiatry has come up with ever.
But I think even adults deserve treatment protocols in which psychotropic drug use is not the first line, but rather done selectively and only when absolutely necessary. Which is far from the case in current practice.
–Rhiannon
Rhiannon,
Thanks for the feedback. I agree with your comments about “pruning” and how this (normal) process is likely to be quite different from what is happening in the brains of patients taking antipsychotics. However, I was simply expressing the argument made in the editorial accompanying the original paper. One must admit that without clear evidence to the contrary it is at least possible that the tissue loss observed in these patients leads to a more functional brain.
Regarding glia, you are absolutely correct; they are not just “support cells,” they provide a vital metabolic and neuromodulatory function. To see them as simply “scaffolding” is patently wrong. Even if it is only glia that are destroyed during antipsychotic treatment, this could be quite disruptive to brain function and neuronal survival.
Finally, regarding the “dangerous disconnect between neuroscience and psychiatry,” I agree that psychiatrists often lack the neuroscience or pharmacology background required to understand in detail how these medications work (which is itself quite frightening), and instead must rely on glossy brochures from pharmaceutical companies or ghost-written journal articles that frequently oversimplify the biology. But that doesn’t necessarily mean psychiatry should take even deeper steps into neuroscience. A psychiatrist who becomes an expert in neurochemistry is, almost by definition, a psychiatrist who pays even less attention to a person’s subjective suffering (“serotonin deficiency,” anyone?). Personally, I think psychiatrists should take a step back– perhaps even widening their disconnect from neuroscience– and start looking at patients as humans and not as brains, transmitters, neurons, and glia.
Dr. Balt,
I like your writing as you appear to be an intelligent, thoughtful doc. You might not think so but both those qualities are rare among docs. Docs are selected to be stupid about life and compliant.
You are a psychiatrist so you may not agree with my opinions but I want to share them with you anyhoo. I think medical care for the mental cases for drug addicts, alcoholics and for the obese is wasted money. These things are not illnesses because people have control over them. Theres tons of stuff about what people can do to be mentally balanced stop drinking, drugging and lose weight. It’s up to them really, We shouldn’t be spending billions of dollars on programs for these selfdestructive people especially since the programs don’t work anyway.
Most mental cases are people who are unhappy with Life. They have issues they need to face. What they don’t need is more and more expensive medication and more and more so-called therapys from about a zillion therapists who make a comfortable living perpetrating the fraud that they are helping.
Pretty much the same goes for drug addicts and alcoholics. They have their own free programs so why spend tax payers dollars on them? They don’t stop until they are ready anyway.
If you are going to tell the truth I wish you would tell the whole truth and nothing but the truth.
Truly yours,
Winston Salem
How utterly glib. You would not be so nonchalant about a 10% loss of gray matter volume if it happened to YOUR brain. If these drugs are so harmless as you imply, why don’t YOU take them?
We live in a world in which anything can happen. Perhaps it will come to pass that I will be able to force you to take these drugs for 10 years whether you want them or not, and then we can take a look at your brain. I have taken quetiapine for nearly 9 years, and my doctor never told me about the mounting body of research indicating the strong possibility of antipsychotic-induced loss of gray matter volume. I found out about it just recently. I was utterly furious, still am. No, it is not mania or psychosis, it is justified outrage at what is clearly professional malpractice.
My psychiatrist was in my opinion either negligent or dishonest or both in her handling of this matter. She should have told me about the potential harm this research suggests may result from long-term administration of atypical antipsychotics. There is absolutely no excuse for this behavior. Did she think I would not find out?
I went to medical school for two years (GWU School of Medicine) before depression put an end to that career, so do not assume I know nothing of your “art”. I took (and passed) the required 2nd year courses in psychiatry and pharmacology. These facts are a matter of record. The theoretical basis of psychiatry is in my view and in the view of many others, including others in the medical profession, weak. Watch out! Your radiology is catching up with your charlatanism.
I live in Greensboro, NC. I will refer to my psychiatrist as “Dr. Jane” because to tell you her last name would be indiscreet (Steiner).
Andrew Bulgin, Greensboro, NC
thats right andrew,I’ve been on seroquel for yrs and its ruining my health,borderline diabetic,cholesterol high,,,I;ve also been on welbutrin before for yrs and it really screwed me up,,now im looking at taking this new drug contrave,,and again probably going to have problems,,and to people who dont suffer from bi polar mania,or depression how the hell would u know,,and the guys comments on drug addiction sounds like something you would here at one of those hate rallys u see at republican rally’s….u people dont know squat about drug addiction,,,,oh we can just stop if we want…what a complete idiot that guy is give me a break please…im struggling with all kinds of mental and drug addiction,,ive been sober now since 2000…and it isnt as easy as “just stopping” and he has know idea what its like for us who are suffering from mental illness….i used to be a fireman and an emt 2,,,so u think id rather be in the position im in now rather than my career,come on dude get real….u dont know the silent hell we live in with these docs,,all these drugs have bad effects,,ive been hospitalized several times due to side effects of these drugs,and they all hurt one way or another….if he had any idea what the hell he was talking about he would would just shut up,,,we live in hell with these drugs,,,and no end in site either they just come out with new crap every day and have no idea what it does or how it makes us feel….
Throw into this that *Cannabis*, or an easily attained compound within it, has been found recently to function as an antipsychotic without major side effects .it becomes obvious that psychiatry is seriously flawed, in fact more so than that is downright inhumane and illogical. It seems to be correct that cannabis could solve a great deal of our ills because it also remedies epilepsy, cancer etc. Psychiatry needs to be flushed down the toilet in its current form
As someone who has experience of being claimed to be schizophrenic and then rabidly drugged by this profession i can tell you that there has been no positives worth the almost wholly negative experience of being on these medications. You are a complete disgrace to uphold the use of these drugs in any form and the facts as to how cannabis itself( that so called demon weed that causes mental illness – according to most of you shrinks) has been found to treat schizophrenia without any side effects highlights in the most thorough way that all of those deathly side effects that have been imposed on so many, often against their will (you slimeballs) has been for practically nought and were entirely unnecessary. You are not a doctor.
Thank you for this post. What source did you use to obtain the information about anti-psychotics pruning the brain?