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by Marzia Delle Piane and Paola Rossi

(Dipartimento di Neuroscienze — Università di Genova, POL.it)

The growing amount of available pharmacological therpies for psychiatric disorders abolished several limits, that were considered unbeatable only few yers ago. In particular, the new atypical antipsycotic drugs appeared superior, compared to classic neuroleptics drugs, in effectiveness against "negative" symptoms of schizophrenia; that is to say, it was possible to gain better success against psychotic .This goal, together with a maintained effectiveness versus positive symptoms, made it possible for us to effectively carry on rehabilitation programs designed to resocialize our patients, not only to control his or her behavior.

It’s true, though, that such molecules do have a massive impact on the patient’s body. Many patients, remarcably those affected by important diseases, like schizophrenia, may assume these drugs for a long time, years often, frequently in association with other treatments. No wonder, then, that accurately evaluating adverse effects of these drugs, besides undoubtable therapeutical effects, has become crucial, being sometimes the key factor for choosing one drug rather than another one.

The new AP drugs has gained great reputation among psychiatrists from this point of view, too, since they seem to reduce some among the most serious side effects of neuroleptics: the reduced incidence of EPSs may be used as an example. Recently, though, a possible link between atypical APs and glucidic metabolism failures has been underlined: the importance and the interest of such problems are clearly shown by the growing amount of literature production about this matter. We report here, as an eample, a paper published by Citrome L. this year (Focus on The clinical ramifications of antipsychotic choice for the risk for developing type 2 diabetes mellitus. Int J Neuropsychopharmacol. 2005 Jun;8(2):147-51.) which underlines the fact that among patients hospitalized within New York State Office of Mental Health psychiatric centres, prevalence of persons receiving both antipsychotic and anti-diabetic medication is 9.5% for men and 14.7% for women (Citrome et al., 2004a). This is substantially higher than the prevalence of diagnosed diabetes among New York State adults. Many explanations have been proffered to explain the higher risk of association with type 2 diabetes mellitus among patients with schizophrenia compared to the general population, including a biological linkage between these two disorders (Ryan et al., 2003), and the unhealthy lifestyles practised by patients, such as a high fat diet, smoking, and lack of exercise (McCreadie et al., 2003). Within the past 3 years, much attention has been placed on the metabolic consequences of using second-generation antipsychotics (Citrome, 2004).

Of these new research lines, the FDA put out a warning about clinical use of such molecules and possible metabolic consequences for patients: it has now become demanding to get a view on the state of the art in this matter.

Many papers from different groups approached initially the question whether or not the increased incidence of diabetes in psychiatric population, especially in schizofrenic patients, could only be attributed to APs or also to a common genetic risk factors shared by psychiatric illnesses and glucose dismetabolism.

Back in 1926, undoubtedly earlier on before neuroleptics were introduced in clinical use, Kasanin J. had focused on changes in glucose metabolism changes in psychiatric patients.More recently, in 1996, Mukherjee S Decina P e coll., followed by Cassidy F. Ahearn E, Carrol BJ. Brought evidences about the fact that patients diagnosed with schizophrenia or bipolar mood disorder have a higher prevalence of diabetes mellitus (17%) than the general population(3,3%). Given these data, other groups tried to analize the possible causes of such a comorbidity.

A recent work from Ryan et al. - Am J Psichiatry; 2003; 160: 284-289 showed that drug naïve patients, at their first psychotic episode, showed a reduced glucose tolerance and a higher insuline blood level.

It also came out that schizophrenic patients showed higher cortisol blood concentration, compared to normal population. Notably, high cortisol blood level promote the development of poor glucose tolerance.

A paper by Bergman et al. confirms the demonstration of the contribution of antipsychotic drugs to body weight increase , which may induce fat tissue hypertrophy: this may cause insuline resistance. The compensation , hyperinsulinemia, could prevent the development of diabetes. It seems now possible that atypical APs relate to an inadequate insuline increase. It still needs to be determined, though, if this poor compensation to insuline resistance plays a central role in the development of diabetes associated to AP drugs prescription. (Bergman RN, Ader M: Atypical antipsychotics and glucose homeostasis - J Clin Psychiatry. 2005 Apr;66(4):504-14.)

Susce MT, Villanueva N, Diaz FJ, de Leon J. too, showed the importance of obesity in schizophrenic patients. (Obesity and associated complications in patients with severe mental illnesses: a cross-sectional survey. J Clin Psychiatry. 2005 Feb;66(2):167-73.)

Furthermore, Newcomer JW reviewed the association between antipsychotic medications and obesity, insulin resistance, and diabetes, including the mechanisms through which these changes might be effected. (Abnormalities of glucose metabolism associated with atypical antipsychotic drugs. J Clin Psychiatry. 2004;65 Suppl 18:36-46.)
Following Bergman RN, Ader M. (Atypical antipsychotics and glucose homeostasis. J Clin Psychiatry. 2005 Apr;66(4):504-14) atypical antipsychotics have been shown to contribute to weight gain, which may well reflect increased body fat deposition. Such increased fat is known to cause resistance to insulin action, although more information regarding effect on insulin action is needed. The effect of these drugs on fat distribution has been clearly shown in animal models. It is known that the normal response to insulin resistance is compensatory hyperinsulinemia, which may prevent diabetes. In animals, there is evidence that the hyperinsulinemic compensation is inadequate in the face of atypical antipsychotic agents. It remains to be examined whether failure of adequate pancreatic beta-cell compensation for insulin resistance plays a central role in the pathogenesis of diabetes associated with this class of drugs. Recently, though, Mellitus D, Krosnick A, Wilson MG. (Clin Ther. 2005 Mar;27(3):320-6 A retrospective chart review of the clinical effects of atypical antipsychotic drugs on glycemic control in institutionalized patients with schizophrenia and comorbid.) focused on comorbidity between psychiatric illness and diabetes, getting to the conclusion that an appropriate antidiabetic therapy is able to maintain a satisfactory glucose homeostasis control in a group of patients suffering form both schizophrenia and diabetes, while carrying on the treatment with atypical AP drugs.

The importance of methabolic variations in patients undergoing treatment with antipsycotic drugs is also supported by the findings of Newcomer JW. (Metabolic risk during antipsychotic treatment Clin Ther. 2004 Dec;26(12):1936-46)who states that metabolic changes in psychiatric patients who receive antipsychotic agents can contribute to the development of the metabolic syndrome and increase the risk for T2DM and CVD.Recently even the Canadian Diabetes Association included schizophrenia among risk factors for type 2 diabetes. Canadian Diabetes Association, 2004[http://www.diabetes.ca/Section_about/atrisk.asp]Buse JB et al. (J Clin Epidemiol. 2003 Feb;56(2):164-70)showed evidences that an increased risk of developing diabetes compared with the AdvancePCS general patient population was observed during treatment with conventional or atypical antipsychotics, wether data from WHO* Database (*World Health Organization) on various glucose metabolism changes show no difference amid different AP drugs. (Haddad PM. Antipsychotics and diabetes: review of non-prospective data. British Journal of Psychiatry (2004), 184(suppl. 47), s80-s86)Also a paper by Lee DW, Fowler RB, Kadlubek PJ, Haberman M.(No significant difference in diabetes risk during tratment with typical versus atypical antipsychotics: Results from a large observational study, Drug Benefit Trends 2002;14(11):46-52) goes in the same direction.There are other results, though, which don’t match with such conclusions, or even suggesting opposite results.

Lambert BL (Pharmacoepidemiol Drug Saf. 2005 Mar 22 e J Clin Psychopharmacol. 2005 Feb;25(1):12-8.) states that exposure to olanzapine or clozapine is associated with a 34-41% increase in the developing of type 2 diabetes among California Medicaid recipients with schizophrenia and compared with older generation antipsychotics, exposure to olanzapine and, somewhat less consistently, to clozapine is associated with an increased risk of hyperlipidemia among people with schizophrenia.Still prospective, randomized trials are needed to confirm these retrospective, observational findings.

Another paper by Farwell WR, Stump TE, Wang J, Tafesse E, L'Italien G, Tierney WM. J Gen Intern Med. 2004 Dec;19(12):1200-5. gets to the conclusion that olanzapine and risperidone use was associated with gaining weight in the first year, but only olanzapine was associated with developing diabetes mellitus.Ananth J, Kolli S. point out the fact that we still miss definitive evidences in order to understand the relationship bvetween Aps and diabetes. These authors think that, although not scientifically proven, available evidence seems to indicate that clozapine and olanzapine may have a higher propensity to induce diabetes compared with other AAP drugs.
Finally, in September 2003, FDA requested a modification on the safety label of each atypical AP, in order to include a warning, to provide additional information about the risk of developing hyperglicemia/diabetes in psychiatric patients undergoing treatments with atypical AP drugs.

FDA suggests that efficacy of a drug needs to be considered among primary criteria when choosing the treatment for a psychiatric patient.

Here’s a list of Aps that have changed their label, in the USA:

• Seroquel • Zyprexa • Risperdal • Geodon • Leponex • AbilifyWe attach here the original text of the warnings given by FDA: Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolarcoma or death, has been reported in patients treated with atypical antipsychoticsincluding Zyprexa. Assessment of the relationship between atypical antipsychotic useand glucose abnormalities is complicated by the possibility of an increased backgroundrisk of diabetes mellitus in patients with schizophrenia and the increasing incidence ofdiabetes mellitus in the general population. Given these confounders, the relationshipbetween atypical antipsychotic use and hyperglycemia-related adverse events is notcompletely understood. However, epidemiological studies suggest an increased risk oftreatment-emergent hyperglycemia-related adverse events in patients treated with theatypical antipsychotics studied. Precise risk estimates for hyperglycemia-related adverseevents in patients treated with atypical antipsychotics are not available. The availabledata are insufficient to provide reliable estimates of differences in hyperglycemia-relatedadverse event risk among the marketed atypical antipsychotics. Patients with an established diagnosis of diabetes mellitus who are started on atypicalantipsychotics should be monitored regularly for worsening of glucose control. Patientswith risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who arestarting treatment with atypical antipsychotics should undergo fasting blood glucosetesting at baseline and periodically during treatment. Any patient treated with atypicalantipsychotics should be monitored for symptoms of hyperglycemia including polydipsia,polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemiaduring treatment with atypical antipsychotics should undergo fasting blood glucosetesting. In some cases, hyperglycemia has resolved when the atypical antipsychotic wasdiscontinued; however, some patients required continuation of anti-diabetic treatmentdespite discontinuation of the suspect drug.Areas that require additional research include, but are not limited to, identification of subpopulations at greatest risk for diabetes mellitus adverse events, exploration of the relative risk for diabetes mellitus adverse events among the different antipsychotics, and evaluation of potential mechanisms of action.



In conclusion:

It has been observed that the prevalence of diabetes in psychiatric patients is higher compared to the general population. Until now, though, mechanisms responsible for such an increased risk are not clear, yet.

Possibile risk factors may be a genetic background, metabolic alterations and some AP drugs.

It’s worth mentioning the high prevalence of a non adequate diet in these patients, particularly rich in carb and fat : such a high caloric income may determine metabolic diseases, like diabetes.

Some clinical trials have been carried out, showing a similar prevalence and incidence of diabetes with different antipsychotic drugs. We still need propspectic studies, with acceptable controls.

It is not possibile, now, to draw any conclusions on APs and hyperglicemia/diabetes. FDA, publishing a warning on all atypical AP drugs, points the attentino on these initial data and underlines the importance of further investigate such matter.


RUSSEL KATZ, (FDA). Exclusive interview by Francesco Bollorino Editor of POL.it

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