Low-dose Strategy Can Benefit Schizophrenics

By Pauline Anderson
The Medical Post, Aug. 6, 1996

TORONTO - After 30 years of what might be called guesswork, researchers have finally found the optimal starting dose for the most popular antipsychotic drug on the market, and it's much lower than is often prescribed. Using positron emission tomography (PET) scans and clinical observations, investigators at the Clarke Institute of Psychiatry have determined that the best starting dose of haloperidol is from 2 mg to 5 mg daily, a far cry from the 10 mg, 20 mg and even 50 mg some doctors use.

Not only is the optimal starting dose much lower than is currently the practice in some clinics, but most patients with schizophrenia can be maintained on this low dose, sparing them troublesome side effects, not to mention unnecessary cost.

Introduced in 1966 before the use of sophisticated scientific trials comparing various drug doses, haloperidol is now the prototype for the 15 or so schizophrenia drugs that act through the dopamine D2 receptors in the corpus striatum. Today, more than 80% of schizophrenia patients are maintained on these drugs, said Dr. Shitij Kapur, a research scientist at the PET centre, and a psychiatrist with the schizophrenia research program at the Clarke Institute.

With no data on optimal doses -- and no such recommended information contained in the Compendium of Pharmaceuticals -- doctors vary widely in their prescribing patterns for haloperidol. Some start patients on 5 mg, but others begin with 10 mg or 20 mg and may even get up to 50 mg/day, said Dr. Kapur.

Dr. Kapur and colleagues studied a 2 mg daily dose in seven mainly first episode psychosis patients diagnosed with schizophrenia. After two weeks, PET scans showed that this dose resulted in a high dopamine receptor occupancy rate. The average receptor blockage level was 67% and ranged from 53% to 74%.

Occupancy rates that are too low could still result in psychotic symptoms while obtaining higher occupancy rates likely wouldn't offer additional benefits. "Obviously the more drug you give, the more you block (the receptor), but you can't block beyond 80% or 90% because then you'd be pretty much maxed out," said Dr. Kapur.

The rate of receptor blockage achieved in the study approaches the optimal level because it leads to clinical response without significant side effects, he said. "Side effects don't show up below 80% but they show up quite prominently beyond 80%, so 80% seems to e a sort of threshold for side effects."

Those side effects can be crippling and are the main reason schizophrenia patients stop taking their drugs. Slow movements and speech, stiffness and tardive dyskinesia are responsible for a drug dropout rate that ranges from 20% o 70% depending on the definition of noncompliance, said Dr. Kapur.

Once the dopamine receptors are close to being totally blocked by the drug, other neurotransmitters start to be affected, adding more unwanted side effects to the equation. Even moderate doses -- 7 mg or 8 mg -- of haloperidol can produce dopamine blockage beyond the optimal level, he said.

The dose regimen used in the study resulted in substantial clinical improvement. Five of the seven patients were considered "much improved" and two "minimally improved" and none exhibited significant extrapyramidal (motor) symptoms.

"It seems from our data that doses of 10 mg to 20 mg or 20 mg to 25 mg are certainly not needed for the majority of patients," said Dr. Kapur. The study results "add to the already increasing body of evidence that low doses work."

The low-dose strategy could be used for most first episode psychosis cases. "We're not just talking about starting low because patients can't tolerate a higher dose; we're talking about starting low because this might actually be the right dose" for most such patients, he said.

The results of Dr. Kapur's PET research were published recently in the American Journal of Psychiatry and have been reinforced in clinic observations by other Clarke staff. According to research scientist Dr. Jiahui Wong, 23 of 33 first episode schizophrenia patients entered into a four-week trial responded to either 2 mg (14 patients) or
5 mg (nine patients) haloperidol. All experienced significant symptom improvement with no side effects.

These patients are "happy" on these doses and their compliance is "much higher" than with more potent doses, said Dr. Wong. Of the 10 who did not respond to lower doses, seven were maintained on 10 mg of the drug and only three patients had to be raised to 20 mg.

Dr. Wong said it's "unethical" to go beyond 20 mg although she recognizes that this is sometimes the practice. "Doctors sometimes just keep drugging patients until they're quiet."

The Clarke research is convincing for first episode psychosis patients, but Dr. Kapur said a 5 mg dose might be better for chronic patients.

For her part, Dr. Wong said it's difficult to lower the dose in patients already on the drug. Their body has adjusted to the dose, their neurons are already damaged, and there's a danger that symptoms will return if the dose is tampered with, she said.

Copyright 1996 Maclean Hunter Publishing Limited
Reprinted with permission.

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