More reasons why to avoid antipsychotic drugs if possible

[Guest guest]

I am posting this since so many " loving " doctors are exploring off label adult

medications for our children with autism. Caveat emptor!!

Published on Psychology Today (http://www.psychologytoday.com)

Charlie Rose and the Mentally Ill Brain

By Whitaker

Created Aug 12 2010 - 1:51pm

On a recent PBS television show hosted by Charlie Rose on the " mentally ill

brain, " Columbia University's Lieberman presented a series of brain

scans of a person with schizophrenia, which showed enlarged ventricles and thus,

as Lieberman told the audience, " loss of brain gray matter. "

(See minute 29:30 of video.) The idea being presented by Lieberman was that

schizophrenia is a neurodegenerative disease, characterized by brain tissue

loss.

In the discussion, Lieberman also implied that antipsychotic medications, in

some way, protect against this neurodegenerative process. The drugs " stabilize

the illness, " he said. But when people " stop taking the medicines, they get sick

again, and when this happens, they have repeated insults to the brain . . . and

this leads to a progression, and the progression, like somebody who has multiple

little strokes, can lead to some decline in which people are not able to recover

to the same level. And if you actually take brain scans over time, you can see

the subtle, perceptible loss of brain grey matter. "

To the public, this is a new paradigm for understanding why antipsychotics are

an essential treatment for schizophrenia. Schizophrenia is a neurodegenerative

illness, characterized by brain tissue loss, and antipsychotics are

" neuroprotective " agents that thwart that pathological process in some way.

Given that this idea is taking hold, it seems worthwhile to check the literature

to see if it is well grounded in science.

MRI Scans

Making sense of MRI studies of schizophrenia patients can be a difficult task,

partly because the results can be so inconsistent, and partly because the

results are confounded by exposure to antipsychotics. However, earlier this

year, Joanna Moncrieff and Leo brought new clarity to this topic by

analyzing the studies based on the patients' exposure to antipsychotics.

Here is a summary of their findings, which they published in Psychological

Medicine.

Studies of chronic patients never exposed to antipsychotics

They identified three studies of schizophrenia patients who were ill for

extended periods of time and were never exposed to antipsychotic medications. In

comparison to the " controls " in the studies, these never-exposed patients showed

" no major differences in global cerebral, grey-matter, ventricular, or CSF

(cerebrospinal fluid) volumes. "

Studies of first-episode patients with limited exposure to antipsychotics

A number of studies have found brain abnormalities in first-episode

schizophrenia patients, and these findings have been seen as proof that the

abnormalities must be due to the disease and not the treatment. But as Moncrieff

and Leo noted in their paper, many of the patients in the first-episode studies

had been on antipsychotics for months, and there is evidence that antipsychotics

may induce changes in brain structures in a short period of time. As such, the

results from first-admission studies -- as a group -- are confounded by drug

exposure.

To counter this problem, Moncrieff and Leo analyzed the results from studies of

schizophrenia patients who were either drug naïve or had limited exposure to

antipsychotics (on average less than four weeks.) They found 18 such studies (in

addition to the three studies discussed above.)

In 13 of them, researchers did not find any differences between the patients and

controls in whole-brain volumes, total grey matter, and CSF volumes. Of the five

studies that did show differences in brain volumes, one included a subset of

patients that had taken antipsychotics for up to 24 weeks, which could have

confounded the results. A second study reported differences in an initial sample

of 18 patients, but then, in a larger sample of 51 patients, no global

differences were found. The remaining three studies found a difference in the

size of the " third ventricle only; " a " trend level reduction in whole-brain

volume; " and " smaller cerebellar volumes. "

Longitudinal studies of patients treated with antipsychotics

In 14 of 26 MRI studies of schizophrenia patients treated with antipsychotics

for periods ranging from eight months to 10 years, the patients " showed a

greater reduction in whole-brain, cortical or grey-matter volumes, or a greater

increase in CSF or ventricular volumes, compared with controls. "

Several of the 14 studies quantified the brain-volume loss. In adult patients,

" grey matter, whole-brain or cerebral volume showed a decline of 1.2% to 2.9%

per year. "

Summing Up The MRI Studies

With the MRI literature parsed in this way, it's easy to see that the studies do

not provide convincing evidence that schizophrenia patients, if they were not

treated with antipsychotics, would regularly suffer " a loss of brain gray

matter. " A reduction in whole brain volumes is not regularly seen in

first-episode patients with limited exposure to neuroleptics, and it was not

seen in the three longitudinal studies of never-exposed patients. The fact that

it shows up in the majority of studies of drug-treated patients simply leads to

this possibility: It could be due to a disease process, or it could be due to

the medication, or it could be due to a combination of the two.

The Effect of Antipsychotics on Brain Volumes

To best assess the long-term effects of antipsychotics on brain volumes and to

distinguish drug effects from disease processes, you would need to run a

long-term study that compared brain volumes in four groups: healthy people on

the medications, healthy people off the drugs, schizophrenia patients on the

drugs, and schizophrenia patients off the drugs. But you can't put healthy

people on antipsychotics and it is considered unethical to withhold

antipsychotics from schizophrenia patients for long periods, and so you can't

run studies of that type. However, animal research and MRI studies of medicated

schizophrenia patients do provide evidence that antipsychotics may cause " brain

gray matter loss. "

In animal studies, typical antipsychotics have been found to cause neuronal loss

and gliosis in the striatum, hypothalamus, brain stem, limbic system and cortex.

In a study of non-human primates (macaque monkeys), a daily dose of haloperidol

or olanzapine for 18 months led to an 8% to 11% reduction " in mean fresh brain

weight compared to controls. "

Next, as Moncrieff and Leo reported, a majority of studies of schizophrenia

patients on the drugs for longer periods found that they had reduced brain

volumes, while in the three longer studies of never-exposed patients, there was

no such finding. Furthermore, researchers have found that gray matter loss

varies according to whether a typical or atypical antipsychotic is prescribed,

and if the drugs did not affect brain volumes, there shouldn't be this

variability. Lieberman and others recently conducted a study of this type,

mapping the cortical changes seen in 36 first-episode schizophrenia patients

treated with either haloperidol or olanzapine for one year.

Here are their results, which they published in 2009:

• In the haloperidol patients, " a dynamically spreading wave of significant gray

matter loss was detected . . . progressive gray matter reduction began in

lateral parietal-temporal cortices by three months, spreading into the

dorsolateral, medial frontal and prefrontal cortices by six months, and

involving most of the frontal cortex by one year after the first psychotic

episode. " The " total loss is severe by 12 months. "

• In the olanzapine patients, " regions of significant progressive gray matter

loss were found at all time points, but these were less intense and widespread.

These changes also evolved in a distinct antatomical trajectory " compared to the

haloperidol-treated patients.

So how should these results be interpreted? Given the effects of haloperidol and

olanzapine in macaque monkeys, you might conclude that both drugs cause brain

gray matter loss in schizophrenia patients, with olanzapine perhaps less toxic

than haloperidol. However, since there was no control group in this study and

thus no mapping of gray matter loss in unmedicated schizophrenia patients, the

researchers concluded that it was also possible that olanzapine was

" neuroprotective, " i.e. that it slowed down the loss seen in the haloperidol

patients (which presumably was due mostly to the disease.) But, they wrote,

without a control group " it is difficult to be sure that the effect is either

due to toxic effects of one drug versus protective effects of another (among

other interpretations), and it cannot be determined what the normal trajectory

of such change is in schizophrenia. "

The Bottom Line

While the public may be hearing that schizophrenia is a neurodegenerative

disease characterized by a loss of brain gray matter, with atypical

antipsychotics neuroprotective against that process, even a quick review of the

scientific literature reveals that it is unclear whether the gray matter loss is

due to the disease, or to the drug, or to a combination of both.

Here's what Moncrieff and Leo wrote in their conclusion : " Overall, there seems

to be enough evidence to suggest that antipsychotic drug treatment may play a

role in reducing brain volume and increasing CSF or ventricular spaces . . .

although it remains possible that the underlying disease process also causes

brain volume changes, we suggest that antipsychotic drug treatment may be

responsible for some of the changes that are usually attributed to

schizophrenia. "

Source URL: http://www.psychologytoday.com/node/46526