Weighty Consequence
Aussie psychiatrist says antipsychotic drugs pile up the pounds
By Jin Paul de Guzman
ONE OF THE CONTINUING CHALLENGES TO PROMOTING MENTAL HEALTH IS THAT PEOPLE DO NOT GIVE IT SO MUCH IMPORTANCE AS PHYSICAL HEALTH. PSYCHIATRISTS HAVE LAMENTED THIS CONDITION OFTEN, SAYING THAT PEOPLE'S UNDERSTANDING OF "MENTAL HEALTH" DOESN'T GO BEYOND THAT OF POP CULTURE-MEDIATED CLICHÉS. WHEN SOMEONE SAYS MENTAL ILLNESS, PEOPLE INSTANTLY THINK OF THE FOLLOWING-THE RAVING MASS MURDERER, THE LAUGHING-ONE-SECOND-CRYING-THE-NEXT SISA, AND THE KID-RAPING DEGENERATE, WHICH, WHILE ILLUSTRATIVE OF SOME SPECIFIC FORMS OF MENTAL ILLNESS, DON'T REPRESENT ITS FULL SWATH.
On the other hand, there is the challenge of making the recovery of the mentally ill run consistent with physical health. Mental illness often puts a strain on the way people conduct their daily lives-amid psychic pain, what happens to the body becomes almost irrelevant to the mentally ill. And so the greater challenge lies in balancing attention to both the physical and mental/emotional, which as the cliché goes, is always easier said than done.
Sometimes, the reason behind physical health problems in the mentally ill could go beyond disregard of the body. For instance, people with schizophrenia already have an increased risk of medical morbidity, specifically heart disease and diabetes. There is also growing evidence that the use of certain antipsychotic agents may be associated with the development of impaired glucose tolerance and type 2 diabetes.
Psychiatrist Simon Burton of Australia's Royal Brisbane Hospital came to the country in January to present the latest evidence on the link between antipsychotic use and the development of hyperglycemia, diabetes, and cardiovascular risk among patients with schizophrenia.
In the Duty to Care study published by the University of Western Australia in October 2001, nearly a quarter of a million Australians who used mental health services between 1980 and 1998 were studied, with special attention given to hospital admission, cancer incidence, and death. It turned out, Burton said, that people with mental illness have a death rate 2.5 times higher than those without. In addition, the number of excess deaths due to heart disease is much higher among the mentally ill.
As for patients with schizophrenia, different studies have shown that their life expectancy is 20 percent shorter than that of the general population-they are 20 times more likely to commit suicide, 30 percent more likely to die from cancer, and have a combined (cardiovascular and respiratory) standardized mortality ratio of 2.25.
Weight Gain
As people have been often told, obesity opens up the floodgates to different diseases-hypertension, type 2 diabetes, and athe-rosclerosis, among others. The risk of death from these conditions is also significantly raised. Now weight loss or weight gain is a possibility among patients with schizophrenia, but antipsychotic medication has some effect on the patients' weight. Especially those patients on olanzapine and clozapine, which, in a study published by Allison et al. in the American Journal of Psychiatry in 1999, showed that these could contribute to a weight gain of 3.5kg or 4kg over ten weeks.
A number of placebo-controlled studies involving specific antipsychotics (ziprasidone, risperidone, olanzapine, and quetiapine) have looked at the incidence of clinically significant weight gain-seven percent or more of the body weight-within eight weeks. Ziprasidone registered the smallest percentage of clinically significant weight gain (9.8 percent), followed by risperidone (18.0 percent). Twenty-nine percent of those on olanzapine showed clinically significant weight gain.
Aside from these, Burton also said that the "trajectory of weight gain is different [among] antipsychotics"-in risperidone weight gain plateaus by the third month, in olanzapine by the first year, and clozapine by the second year.
What brings about weight gain when a patient is under antipsychotic therapy? The blockade of serotonin (specifically 5-HT2c/5-HT2a) and histamine receptors, which is a common characteristic of many antipsychotics, has been known to have an effect on the satiety center in the hypothalamus which may bring about continuous eating and thus weight gain.
Since the American Heart Association declared that weight gain is "a major modifiable risk factor for coronary heart disease," instituting intervention methods to prevent or control it is necessary. Burton said that one must be aware of the risk factors facing the patient. He added, "once you've gained weight, it's almost very difficult to lose." Aside from changes in diet and physical activity, the use of appropriate antipsychotic medication may also help. If for example the patient is already obese or has heart problems, other specific intervention procedures may be started.
Lipid Changes
Burton said that lipid levels are an important risk factor in cardiovascular disease. In addition, elevated triglycerides may lead to insulin resistance and the development of metabolic syndrome, or syndrome X. Recent studies have looked into the "hypertriglyceridemic waist concept" in which a waistline of over 96cm, hyperinsulinemia, elevated apolipoprotein B, and raised low-density lipoproteins indicate the presence of this syndrome.
A number of studies have looked into the effects of antipsychotics on lipid levels, but what is commonly observed in these studies is that clozapine and olanzapine often have statistically significant results in elevating fasting trigyceride and cholesterol levels.
Diabetes
With the incidence of the so-called lifestyle diseases-specifically diabetes-growing every year, the risk of developing cardiovascular, cerebrovascular, and other diseases have also gone up. In recent years the use of certain antipsychotic agents has also been linked to impaired glucose regulation. Evidence exists that diabetes is common in patients with schizophrenia even before they start medication. And the presence of abnormal glucose control and diabetes among patients with schizophrenia raises the risk or severity of tardive dyskinesia and worsens their clinical status. That's aside from their having to contend with psychosocial problems.
Burton said that among conventional antipsychotic agents, diabetes incidence is higher with low-potency antipsychotics like chlorpromazine but lower with high-potency antipsychotics like haloperidol. As for the newer agents, clozapine and olanzapine have the most number of studies showing their relation to abnormal glucose regulation, exacerbation of type 1 or type 2 diabetes, new onset type 2 diabetes, and diabetic ketoacidosis. These effects, it must be noted, don't necessarily come with weight gain. Fewer are the observations linking risperidone and ziprasidone to impaired glucose regulation and diabetes. Available evidence shows that these agents rarely affect glucose regulation, and at lower levels if ever they do.
The risk of developing type 2 DM is already high among schizophrenics and certain antipsychotics have greater association with IGT and type 2 DM. A 1999 study in Clinical Psychiatry News involving 396 patients from Pittsburgh showed that those on clozapine had the highest prevalence of type 2 DM (15.5 percent), followed by those on olanzapine (11 percent). Reports pooled by Koller et al. (from January 1990 to February 2001) using the United States Food and Drug Administration MedWatch showed 384 clozapine-associated diabetes, of which 242 were definitive new-onset and 54 preexisting DM that had suffered exacerbation. There were also 80 cases of metabolic acidosis/ketosis and 25 deaths during hyperglycemic episodes. Of the new-onset cases, most appeared within the first six months of clozapine therapy.
Koller et al. studied these data, and concluded that the "number of reports, temporal relation to treatment initiation, young age, and prompt reversibility on drug withdrawal in some patients, suggests, but does not establish, a causal relationship to the drug." In addition, there was no association between dose and severity, acidosis or time of onset.
In a separate study by Koller et al., pooled reports (January 1994 to May 2001) from US-FDA MedWatch, olanzapine-associated diabetes got 237 cases, 188 of which were new-onset DM. Of the 188, 73 percent presented with DM by the sixth month of olanzapine therapy. In addition, 80 patients had ketosis/acidosis and 15 died. One of the significant findings was that cessation or decrease of olanzapine intake improved DM control in 78 percent of patients. Also, there was a recurrence of hyperglycemia in eight out of 10 cases that restarted olanzapine therapy. Koller et al. concluded that "these results suggest a causal relationship between olanzapine and the development or worsening of diabetes." At the end of the study until February 2002, 52 more cases were identified, with results conforming to Koller's findings. Eight of these new cases died.
A more recent study investigating the relation of olanzapine with diabetes was published by Carol Koro in the British Medical Journal in August 2002. The study sifted through 3.5 million patients between 1987 and 2000. 19,637 of these patients had been diagnosed and treated with schizophrenia, and 451 had diabetes.
It showed that patients on olanzapine had an increased risk of developing diabetes compared with people not on antipsychotics, with an odds ratio of 5.8. What Burton found "astounding" about the results was those on olanzapine had a mean weight gain of 4.15kg. The study concluded that olanzapine is associated with a "clinically important increased risk of developing DM," and that doctors should consider the metabolic consequences of olanzapine before and during treatment. Burton added: "We should be taking more responsibility for the general health of the patients we are looking after."
Burton said that small increases in glucose levels are a more common outcome in patients on antipsychotics rather than large increases and actual DM. But is this important? "I believe it is," Burton said, adding that they have "long-term detrimental cardiovascular outcomes resulting from small increases in glucose below the threshold of DM."
Last Words
And so based on the results of the studies, Burton recommended that patients be screened for diabetes risk prior to starting medication. During antipsychotic therapy, Burton recommended regular checking of body weight. He also saw the necessity of submitting to at least annual fasting plasma glucose test or oral glucose tolerance test, but if the patient is at higher risk, this could be done a little more often. Increases/abnormalities in plasma glucose or lipids should also be noted, as well as the risk of ketoacidosis. Lastly, a "meaningful dietary intervention" and physical activity should be instituted to fight weight gain.
As for the use of the appropriate medication, Burton stressed that antipsychotic medication should be tailored to individual needs, and if diabetes risk were a concern, he recommended the use of "low-risk" antipsychotic in favor of the "high-risk" antipsychotic. The patient's condition should be consistently monitored, and if necessary, intervention programs started. Lastly, lifestyle issues should be addressed, including diet modification, involvement in physical activity, and smoking cessation.
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