Schizophrenia Research Blog: September 2004 Archives

September 27, 2004

Incidence of Newly Diagnosed Diabetes Attributable to Atypical Antipsychotic Medications

Incidence of Newly Diagnosed Diabetes Attributable to Atypical Antipsychotic Medications

Douglas L. Leslie, Ph.D., and Robert A. Rosenheck, M.D.
Am J Psychiatry 161:1709-1711, September 2004

This is an article that attempts to clarify whether there is a direct relationship between diabetes and the use of atypical or second generation antipsychotics. Diabetes, which is a disease in which the body is unable to regulate the level of sugar in the blood, is important because it is a very strong risk factor for complications such as heart disease/heart attacks, blindness, kidney failure, limb amputations, and many other maladies. The prevailing wisdom, has been that while there is definitely a substantially higher proportion of people with schizophrenia who also have diabetes, there is apparently also a link between some of the newer antipsychotic medications and development diabetes irrespective of the already increased risk. It has been shown that particular antipsychotics have higher weight gain risk (clozapine, olanzapine and quetiapine) and this weight gain risk leads to increased risk of diabetes (or so the theory goes...) This is not terribly surprising because these medications share a common molecular ancestry that is different from the other antipsychotics. So, this paper seeks to clarify exactly what the risk of developing diabetes is by looking retrospectively at a large volume of data from the VA system (veteran’s affairs.)

The authors screened over 70,000 patients through the VA records and removed patients who either already had a diagnosis of diabetes or had demonstrated that they did not have adequate medical care (by not having had a recent primary care visit.) After removing those people, they had over 40,000 subjects left. They followed these subjects for a 3 month interval in which they determined the antipsychotic the patient was taking steadily. Of the patients that met that criterion, they followed them for an additional two years and counted up the number that developed diabetes in that time. The result was that over 4 percent of the patients developed diabetes which is nearly 10 times more than the general population. However, they were only barely able to note a statistical difference between medications in their liability towards causing diabetes. Only clozapine and olanzapine showed an increased risk of diabetes compared to the general group. The authors concluded that those medications did confer an increased risk, but a small one and attributed the overall increased risk of diabetes to other aspects of schizophrenia that have yet to be fully described but could be overall poor diet, poor medical care followup, low socioeconomic status and low exercise amounts.

It is important to note the limitations of the study. First, it was retrospective and therefore not as valuable as a study that seeks to answer a question with data that does not already exist. Also, the VA system does not necessarily represent the general population (higher amount of male patients, particular socioeconomic status, etc.) If someone was diagnosed with diabetes by an outside of the VA doctor, it would not necessarily have been reflected in their records. Also, there were a very large number of patients who were excluded from the study and so they may have already developed diabetes from their medication perhaps and we would not know. Lastly, the three month window that they used to determine which antipsychotic the patient was on may or may not have ultimately been the same as the medication they were on during the rest of the followup.

So, we know that diabetes is a large problem for people with schizophrenia. It may be that the medications are at least partially responsible, but we don’t know for sure. It is likely that olanzapine and clozapine confer at least a slightly increased risk compared to the other drugs. This goes along with their increased risk of weight gain. Future studies, which would be better if they were prospective (the question was asked before the data collected) and then we could get a better idea. However, this study does further add to the importance of having either the psychiatrist or primary care doctor follow a patient very closely to keep an eye out for the development of diabetes before they manifest the full blown illness.

Here is a link to the article on pubmed

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September 15, 2004

Reporting of Safety for Medications

Safety reporting in randomized trials of mental health interventions.

Papanikolaou PN, Churchill R, Wahlbeck K, Ioannidis JP.
Am J Psychiatry. 2004 Sep;161(9):1692-7.

Prior to a medication being offered to the public there are scientific procedures known as randomized controlled trials (RCT) that are used to test the safety and effectiveness of a medication (Click here for more information about different types of clinical trials). In psychiatry, it is unclear of how adequate the reporting of safety information is in publications of randomized trials. As such, the authors for this study explored whether the reporting of safety information, including withdrawals due to toxicity, clinical adverse events, and laboratory-determined toxicity, is neglected in randomized controlled trials of therapeutic and preventive interventions.

The authors randomly selected 200 entries from a European registry known as PsiTri which holds information about controlled trials across the field of mental health. In 2002 this registry contained 16,504 controlled trials. For this study, of the 200 randomly picked entries, 142 were randomized trials of medications or other types of interventions. They analyzed these entries for adequacy and relative emphasis of their content on safety issues.

They found that majority of the eligible trials were for medications. Among these medication trials, only 21% had adequate (as defined by their qualitative and quantitative measures) reporting of clinical adverse events and only 16% had adequate reporting of laboratory-determined toxicity, while 32.0% reported both the numbers and the reasons for withdrawals due to toxicity. They also found that medication trials devoted 1/10 of a page in their results sections to safety, and 58% devoted more space to the names and affiliations of authors than to safety. According to the authors, none of non-medication trials had adequate reporting of clinical adverse events or laboratory-determined toxicity. They also found a neglect of safety information in long-term trials and less space had been given to safety in trials conducted in the United States. On a more encouraging note, schizophrenia trials were found to devote more space to safety than trials in other mental health areas.

Overall, the authors suggest that safety reporting is largely neglected across trials of mental-health-related interventions. They suggest that this neglect of safety in mental health-related trials is similar to what has been reported for other medical fields including HIV therapy, hypertension in the elderly and nonsteroidal anti-inflammatory drugs for rheumatoid arthritis. The results from this study are discouraging since many patients can be unaware of adverse effects of medications even if it is rare might want to know the potential toxicity of various medications. Yet, the study highlights the need for further development and reporting of evaluation tools that can appraise safety reporting in specific categories of trials.

However, there are several limitations to keep in mind about this study. Firstly, from these results it is difficult to decide whether the lack of safety information in a published article was because such information was never collected or whether it was collected but not reported. Secondly, qualitative and quantitative factors used to determine adequacy can be different based on the investigators. Even though this study used previously validated tools, other criteria for adequacy may have found different results. Another limitation is that it is not easy to make attribution and causal claims in behavioral, psychological, or social interventions, which might account for the underreporting in these cases. Fourthly, the registry that was used does not contain all trials and most samples were small (which limits power for safety). Finally, mental health outcomes by their very nature are an important part of benefits and toxicity; and as such these effects may be difficult to tease apart.

This study was supported by a concerted action grant from the European Commission Quality of Life Programme.

Click here to find this article on PubMed

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September 14, 2004

Insight and Violence

Insight and Its Relationship to Violent Behavior in Patients With Schizophrenia

Buckley PF, Hrouda DR, Friedman L, Noffsinger SG, Resnick PJ, Camlin-Shingler K.
Am J Psychiatry 161:1712-1714, September 2004

People with schizophrenia differ on the degree to which they are aware of having an illness and this can impact behavior. A small percentage of those with schizophrenia get violent and it seems that this violence is most likely to happen during periods of active psychosis. Doctors and legal experts go back and forth as to whether patients can be held accountable for such violent acts while they are actively psychotic. Similarly, the role of “insight” into ones illness has also been debated. “Insight” into illness is defined as ‘an awareness of having an illness, an attribution of recognizable symptoms of that illness and an appreciation of the need for treatment’.

This study looked at the extent and pattern of insight deficits in patients with schizophrenia who are violent. Using different questionnaires, the authors asked 115 patients with schizophrenia who were in a jail or court psychiatric clinic to answer questions about their symptoms, illness severity, insight into illness and insight into the legal consequences of their illness ("forensic insight"). They also included a sample of nonviolent patients with schizophrenia in order to have a comparison group. The authors report that they went through reviews by institutional review boards, extensive discussions with jail warden and municipal judges and social workers in order to protect the rights of the patients.

The results confirmed that the overall risk of violent crimes committed by people suffering from schizophrenia is small and that most incidents are of low lethality. In this study, the most common offense by violent patients with schizophrenia was felonious assault, with 1/3 of offenses being committed against a law enforcement officer and ½ against a known person or relative. The majority of violent patients also had active psychotic symptoms and were abusing substances at the time of the violent incident. Also, compared to the nonviolent group, violent patients had poorer functioning and had a more prominent lack of insight which was related to having a lack of forensic insight (ie a lack of awareness of the legal consequences of their actions). This distinction is important because legal debates regarding competency are often based on the extent to which illness-related variables affect the understanding of the crimes committed by individuals with mental illnesses.

This study suggests that for patients with a history of violence it may be helpful to try interventions (eg cognitive behavior therapy) that focuses on helping improve insight into illness and the legal consequences of the illness. Such medication and psychological treatments can also be preventive in helping improve insight and possibly avoiding future acts of violence during psychotic episodes.

This study was funded by the Theodore and Vada Stanley Foundation.

Click here for the PubMed Link to this article

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September 06, 2004

low dose vs higher dose haldol in first episode schizophrenia

Oosthuizen P, Emsley R, Turner HJ, Keyter N. A randomized, controlled comparison of the efficacy and tolerability of low and high doses of haloperidol in the treatment of first-episode psychosis The International Journal of Neuropsychopharmacology (2004), 7:125–131

This study was conducted to determine which of two doses of haloperidol (Haldol) would be more effective for patients who are new to schizophrenia. In America, we are quick to go to second generation antipsychotics like Risperdal or Zyprexa, but outside of the US, Haldol is still used frequently because of its cost effectiveness and its high potency. People often stay away from Haldol because of the greater risk for side effects like tardive dyskinesia (a movement disorder) and other long term side effects. Also, since Haldol is older and off patent, it is not marketed and can sometimes be forgotten. There are some who argue that the new antipsychotics are only marginal improvements and therefore we are quick to ignore Haldol. Anyways, regardless of the debate, these authors wanted to know if a higher dose of Haldol was better to give or if it would be just as effective but more likely to give side effects.

The authors chose to compare a 2mg per day of Haldol group versus an 8 mg per day group. They came up with those doses based on previous data that suggested that 8 mg was a threshold dose for the initiation of side effects. The authors ultimately found that 2mg and 8mg were equally effective but that the 8mg group did have some higher side effects. One side effect was an increase in prolactin (a hormone that is involved in production of breast milk and in growing breast tissue.) They also showed that both groups had movement disorders (called EPS or parkinsonian movments) but that 8mg was worse than 2mg. They also thought that the 2mg did marginally better on negative symptoms than did the 8mg group.

Overall, this study is interesting because in many situations it is worthwhile, though debatable, to consider starting with Haldol first when someone has new symptoms requiring treatment with an antipsychotic. While it is probably better to try a 2nd generation antipsychotic first when available one can see treatment effects from Haldol. It would be better based on these data to start at 2mg per day than a higher dose though individuals vary such that it may be necessary to start at 5mg daily or higher doses if the psychotic symptoms don’t remit. If you or someone you know is on Haldol, you should not consider changing the dose based on this study but if you have questions you can ask your doctor.

This study was supported by the Medical Research Council of South Africa.

Click here to link to the article on Pubmed

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Folate, homocysteine, and negative symptoms in schizophrenia

Goff DC, Bottiglieri T, Arning E, Shih V, Freudenreich O, Evins AE, Henderson DC, Baer L, Coyle J. Folate, homocysteine, and negative symptoms in schizophrenia. Am J Psychiatry. 2004 Sep;161(9):1705-8.

This is an article that tries to look for an explanation for why patients with schizophrenia have negative symptoms. Negative symptoms are considered the symptoms of schizophrenia that can be very debilitating but are often inaccurately not thought of as the primary symptoms of the disorder. Examples of negative symptoms are a flat or blunted affect (affect is the way someone demonstrates their emotions externally), lack of motivation, poor personal hygiene, decreased cognition (ability to problem solve, etc.), difficulty with interpersonal relations, etc. The authors in this study propose that vitamins in our blood, folate (folic acid) and homocysteine, might have a role in the development of these symptoms.

Folate and homocysteine are vitamins that help with particular reactions in the body and brain. Low levels of folate can be associated with problems with nerves (neuropathy) and in newly pregnant women, low levels of folate are associated with birth defects like spina bifida. Homocysteine is a molecule that helps with various reactions in the body that impact how amino acids are processed. Elevated homocysteine is associated with increased blood clots and strokes.

In patients with schizophrenia, the authors noted that they had a lower average level of folate compared to a population of people without schizophrenia. One possible explanation for the difference may be that people with schizophrenia smoke cigarettes more than the general population and cigarettes may lower folate levels. Also, people with schizophrenia, and particularly those with prominent negative symptoms, may have difficulty eating the green leafy vegetables where one might get folate into their diet. Thus, decreased folate could actually be a symptom of the negative symptoms rather than a possible cause. With homocysteine, the authors did not find that it played a role in negative symptoms.

This was a small study and the results do not give a clear picture for the role of folate in schizophrenia. However, it is possible that in the future more research could be done of the role of folate and clinical changes could be determined at that point. At this point, taking supplemental folate has not been shown to improve negative symptoms, however it is a relatively safe vitamin (it is in every woman’s multivitamin) and so it would be a safe intervention to try with your doctor’s permission.

Supported by NIMH grants MH-02025 (Dr. Goff) and MH-60450 (Dr.
Coyle) and by an Independent Investigator Award from the National
Alliance for Research on Schizophrenia and Depression (Dr. Goff).

Here is a link to the article on Pubmed

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