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Bitter Pills, Better Pills?

Posted on July 26, 2010 | No Comments on Bitter Pills, Better Pills?

The world of people with psychosis has been described as frightening, lonely and tormented. The technical definition of psychosis does not even begin to capture the despair of those who suffer from it. Psychosis refers to a group of disorders that affect the way a person thinks, feels and understands, such that the affected individual may appear to have some loss of contact with reality. There are hallucinations end delusions — seeing or hearing things that others cannot or do not perceive. Because of such manifestations, there is frequent disruption of relationships, jobs and day-to-day functions. They are unable to keep jobs or enjoy the company of others, even friends and family. Sadly, it affects people who are at the prime of their lives, affecting mostly young adults.

For many years, people with psychosis literally had no hope. They were marginalized, or worse, institutionalized or locked within their own homes for fear of either harming others or themselves. It was also a fear of the unknown — many were thought to be possessed by evil spirits or simply, insane. If others did not lock them up, they themselves gradually withdrew from other people — their minds being their own prisons.

How Antipsychotics Work
The elucidation of the nature of these disorders — that they could be caused by chemical imbalances in the brain — led to the development of antipsychotic drugs. For many, these drugs were almost a miracle. With proper medication, many people with psychosis could lead fruitful lives as fully functioning members of society.

These antipsychotic medications work by trying to restore the balance of two major chemicals (“neurotransmitters”) in the brain, serotonin and dopamine. The earliest drugs are called the first generation or “conventional” antipsychotics. These are still widely available and are very effective in controlling hallucinations and delusions, the so-called positive symptoms of psychosis. However, they are not very effective in adequately alleviating the “negative” symptoms (e.g., withdrawal and apathy) and may have some intolerable side effects, foremost of which are movement disturbances that make the users of these drugs walk, talk and move like robots.

Such side effects have led to emotional distress, diminished function, further stigma and non-adherence to the intake of the drugs. The effort to find more effective medications with fewer and less severe side effects led to the development of the second-generation or “atypical” anti-psychotics. They were not only more effective in controlling the symptoms of psychosis but were perceived to be safer and more tolerable.

This would have been the end of the story — people with psychosis content with the newer medications. But confidence in these drugs was again eroded by reports of the development of high blood sugar, frank diabetes and even diabetic emergencies among people receiving antipsychotics, especially among those using drugs of the atypical class. Do these drugs really cause diabetes?

Antipsychotics and Diabetes
Diabetes among people with psychosis is not only due to drugs. People with psychosis have an inherently higher risk of developing metabolic abnormalities including diabetes, obesity, and high cholesterol levels. Data from several studies suggest that the occurrence of both diabetes and obesity among individuals with psychosis is 1.5 to 2 times higher than in the general population.

Also, the risk of dying from heart diseases is already greater among people with psychiatric diseases probably due to physical inactivity and higher rates of smoking; drug-induced diabetes could further increase this risk. The reason for the association between psychosis and these metabolic problems is unclear, but again the sedentary behavior of patients with psychiatric diseases may partly explain this relationship. The introduction of the conventional antipsychotics, and much later the “atypical” anti-psychotics appeared to increase still further the prevalence of diabetes in this population. Thus, the drugs by themselves have caused much concern as they may contribute to significant shortening of the life span of those who take them.

How common is this problem? Some studies cite that individuals taking these drugs are 1.6 times more likely to develop diabetes compared to those not taking any of these drugs. Other studies found that as much as 30 percent of patients taking the atypical antipsychotics developed diabetes. Although concerns about these drugs started with case reports, with even a few deaths due to diabetic emergencies, the association is now clearer with studies on larger groups of patients using these drugs.

Not all antipsychotics increase the risk of diabetes to the same extent. The risks have been shown to be higher with olanzapine and clozapine (“atypical” antipsychotics), and also “low potency” conventional anti-psychotics (Table 1). Lower risk has been seen with risperidone (atypical) and the high potency conventional antipsychotics.

How do antipsychotic drugs cause these metabolic problems? The mechanisms causing these adverse effects are not well understood but several theories have been proposed. One of the major factors causing diabetes mellitus in this population is the excessive weight gain observed with the intake of these drugs especially the atypical agents. Hunger and satiety (or the feeling of fullness during meals) may be altered in people taking the atypical antipsychotics because of the binding of these drugs to the brain receptors implicated in the control of appetite and weight gain. The weight gain may account for many of the metabolic complications seen with these drugs such as insulin resistance (or failure of insulin to effectively lower down blood sugar), diabetes and high cholesterol levels. There is, however, considerable variability in weight gain among the antipsychotic drugs; clozapine and olanzapine cause the greatest weight gain, risperidone and quetiapine moderate gain, and aripiprazole and amisulpride the least gain.

The weight gain over 10 weeks of therapy can vary from as little as 0.5 kg to as much as 5.0 kg in some studies. Limited data even suggest that most of the weight gained is fat. There are however many patients who do not gain much weight but still develop insulin resistance.

Another mechanism by which these drugs could cause diabetes is the development of pancreatitis or swelling of the pancreas, the organ that produces insulin. Acute pancreatitis is an undesirable side effect known to be associated with the use of atypical antipsychotics, again seen most commonly with clozapine, followed by olanzapine, and then risperidone.

Finally, aside from inhibiting the action of insulin, these drugs may also block the release of insulin from the pancreas, leading to a form of insulin deficiency or shortage. The mechanisms as to how these drugs cause these changes in the pancreas are not known.

Caring for Patients on Antipsychotics
How then should individuals taking these drugs be monitored? Before starting antipsychotics, careful evaluation of the risk of developing diabetes or other metabolic problems should be done. These individuals and their family members should be asked about a history of obesity, diabetes, hypertension or heart disease.

Weight and height should be taken to calculate the body mass index, along with the waist and hip circumference, which are measures used to determine the presence of obesity. Blood pressure should also be taken, along with blood tests for fasting blood sugar and lipids (or cholesterol).

Those who are overweight or obese, or who have diabetes should receive counseling about nutrition and physical activity. Those with diabetes should already receive specific treatment from trained physicians. Health professionals, caregivers or family members of patients who will receive antipsychotics should be educated about the signs and symptoms of diabetes.

Weight should be closely monitored. Fasting plasma glucose, lipid levels, and blood pressure should be assessed three months after initiation of antipsychotic medications and if normal, annually thereafter or more frequently for those who have a higher baseline risk of developing diabetes.

How about those who already have diabetes before initiation of antipsychotic medications, or those whose diabetes could have been drug-induced and is difficult to control? Experts recommend switching to antipsychotics that are not associated with significant weight gain or diabetes mellitus. However, such changes should be under close supervision of the patient’s psychiatrist as these alterations in the drugs may also worsen the symptoms of psychosis. Truly these antipsychotic drugs are of great benefit to a wide variety of individuals with psychiatric problems. But along with monitoring effectiveness in controlling the symptoms of psychosis, there is a need to screen and monitor the users of these drugs for the development of diabetes, obesity and high cholesterol levels.

Hopefully with these strategies, these metabolic disorders can be picked up and prevented or treated earlier. These steps are needed so that those who take these drugs can continue to enjoy the benefits without worrying about side effects. And maybe, the person with psychosis could become truly free of fear from both his affliction and its treatment.

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