Schizophrenia Research Blog: November 2004 Archives

November 22, 2004

mirtazapine to help with akathisia?

Efficacy of Low-Dose Mirtazapine in Neuroleptic-Induced Akathisia: A Double-Blind Randomized Placebo-Controlled Pilot Study

Poyurovsky, Michael MD; Epshtein, Svetlana MD; Fuchs, Camil PhD; Schneidman, Michael MD; Weizman, Ronit MD; Weizman, Abraham MD

Journal of Clinical Psychopharmacology: Volume 23(3) June 2003 pp 305-308

Antipsychotic medications are very useful in the treatment of psychosis and schizophrenia, but they have numerous side effects that need to be watched for and treated. While the side effects are generally manageable, it is important to observe and know when they need to be treated. One of the more distressing side effects that can occur, often near the beginning of antipsychotic treatment, is akathisia. Akathisia is a state of severe restlessness in which people feel as though they are “coming out of their skin.” This is more than just feeling that one can’t keep still, it is uncontrollable and incredibly disturbing. Akathisia has been blamed for suicides in which people feel that they just unable to control their bodies from the severe restlessness. Akathisia is a side effect of other psychiatric medications including antidepressants most significantly.

There are several treatments that are used for akathisia. The use of beta blockers (propranaolol, metoprolol and atenolol in particular) have been shown to have benefit in slowing people down. Other drugs, like the anticholinergics (like benztropine or Cogentin). Mirtazapine is a unique drug that acts at many different receptors for neurotransmitters (the chemicals that create activity in brain cells.) It is used typically for depression and has main side effects of weight gain and sedation. In this protocol, sedation was noted, but weight gain was not a problem because the treatment was only for five days.

In this study, the authors looked at 26 people who had akathisia induced by their antipsychotic medications. Patients were either treated with placebo or mirtazapine (randomly assigned, and “double-blind” meaning that neither the patients nor the raters knew who was receiving which) for five days. A placebo was used to identify if there was any placebo effect in which someone improves because of the minds ability to make people better because they think they are on active medication and to see if the actual medication is more powerful than that effect.

The authors found that mirtazapine was effective in the treatment of akathisia induced by antipsychotics. In this protocol, sedation was noted as a side effect with the mirtazapine, but weight gain was not a problem because the treatment was only for five days. 53% of the patients’ akathisia improved which is higher than is generally been reported with the other treatments mentioned above. However, it is impossible to directly compare results unless part of the same study, but it suggests that mirtazapine is at least as effective as other known treatments. The authors also noticed a small improvement in other movement related side effects (EPS) that can be seen with antipsychotics, but they were unable to say if that was clinically significant, but may be worth looking at in the future.

Click here to view the abstract on PubMed

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Mirtazapine to help with negative symptoms?

The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-controlled study.

Zoccali, Rocco; Muscatello, Maria Rosaria; Cedro, Clemente; Neri, Pietro; Torre, Diletta La; Spina, Edoardo; Rosa, Antonio Enrico Di; Meduri, Mario.

International Clinical Psychopharmacology. 19(2):71-76, March 2004.

Negative symptoms of schizophrenia (blunted affect, poverty of thought content and speech, avolition or apathy and social withdrawal) continue to be a substantial problem that currently have no consistent treatments. While there is some data for various behavioral treatments as well as some limited success with various medication interventions. This is another small study that uses an antidepressant to help treat negative symptoms. Antidepressants are compelling drugs for this purpose because the features that are most prominent in negative symptoms of schizophrenia also resemble prominent symptoms of depression. However, the use of older antidepressants such as the class called “tricyclics” had too many side effects and interactions with antipsychotic medications to be safe or effective. Other classes of antidepressants such as MAO-I (monoamine oxidase inhibitors) also had severe interactions with medications and foods and are rarely used in general but are never used with schizophrenia. Lastly, other trials have been done with stimulants but those medications are worrisome because they can induce psychosis in people who have never had it and therefore are especially dangerous in those that are prone for psychotic experiences. Some trials have been done with the SSRI (selective serotonin reuptake inhibitors) which are the most common antidepressants, but the data has not been convincing. This study looks at mirtazapine (Remeron® in the US) which is unique in its action and targets several very specific receptors in the brain and different neurotransmitters (the chemicals that signal brain cells to do different activities.)

This study utilized a well designed protocol to evaluate the effect of mirtazapine on negative symptoms. It was a double blind (neither the patient nor the raters knew the treatments the patients were on), randomized (anybody could have gotten placebo or active drug), and was controlled with placebo (so that it could be compared for possible placebo effect). At the beginning of the study, all the patients were evaluated and found to have the same average amount of symptoms between the groups. Both groups were generally free of positive symptoms (delusions, hallucinations, paranoia, etc.) All the patients were being treated with clozapine for their schizophrenia indicating that these were chronic patients as clozapine is generally reserved for people who have failed other treatments.

The authors found that overall patients with the mirtazapine did somewhat better than those who received the placebo. The results were statistically significant and borderline clinically significant (meaning that the groups were different, but the difference was minor in the overall treatment of the patients.) The authors postulated that maybe because mirtazapine and clozapine work in similar ways that they may be beneficial when used together but that was just a theory.

Overall, more research will need to be conducted on negative symptoms. Perhaps this might be another medication you might ask your doctor about if negative symptoms are a prominent problem. However, mirtazapine is not without its side effects. It can be very sedating at times and also is associated with weight gain. The sedation effects often go away with a higher dose, but the weight gain can be a persistent problem which can be especially troublesome given the weight gain issues of antipsychotics, particularly clozapine, quetiapine and olanzapine.

Click here to access the article on PubMed

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November 15, 2004

Risk from pain killers?

Association between prenatal exposure to analgesics and risk of schizophrenia.

Sorensen HJ, Mortensen EL, Reinisch JM, Mednick SA.
Br J Psychiatry. 2004 Nov;185:366-71.

Background: Along with genes, there are many environmental factors that may increase risk for schizophrenia. Some studies have suggested there is greater risk for developing schizophrenia if an unborn child (prenatal) is exposed to viruses such as influenza. The disturbances in the brain and spinal cord that may occur prior to birth in a fetus may increase the risk for schizophrenia. However, this is still debated since there are researchers who have argued that it is still unclear whether prenatal exposure to influenza influences schizophrenia. The authors in this study wanted to further clarify this relationship, but in particular they were interested in the medications that a mother takes during pregnancy and its effects on the babys later risk for developing schizophrenia. They were particularly interested in a group of medications known as analgesics which are used to reduce pain (e.g. Aspirin).

Method: This was a Danish study that used data that had already been collected in their Copenhagen Perinatal Cohort and the Danish Psychiatric Central Register. They had information about exposure to pain relieving medicines and psychiatric hospitalizations for 7999 individuals (4098 males and 3941 females). They collected mothers reported use of medication through prenatal and postnatal interviews for any medications taken for at least 5 days during pregnancy. They included both prescribed analgesics and pain relievers bought over the counter, but they were not able to separate medications used for treating fever from those used for treating pain. So a mixed group of pain relievers was used ranging from Aspirin to morphine. They made statistical adjustments for parental history of schizophrenia, second-trimester viral infections, other drug treatment during pregnancy, pregnancy complications, parental social status and parental age.

Results: They found that in a risk set of 7999 individuals, there were 1.5% cases of schizophrenia. Interestingly, prenatal exposure to pain killers in the second trimester was associated with an elevated risk. In other words, the estimate of the risk of schizophrenia was more than four times greater in babies who were exposed to pain medications in the second trimester (the association was slightly stronger in females than in males). This suggests that the second trimester is a time when the immature fetal brain is particularly sensitive to a range of environmental influences. However, only 6.9% of the total group with schizophrenia had been exposed to analgesics in the second trimester, so these findings need to be interpreted cautiously.

This study found an unusually high risk of schizophrenia (11.1% and 8.9%, respectively) in the small subgroup of children from mothers who were treated with morphine or opioid pain killers. This could be because of medication related effects, but since this was such a small subgroup of the overall group of mothers, we need to be careful when making generalizations about this morphine finding. Maternal intake of psychiatric drugs during the second trimester was also correlated with intake of pain medications in the same period. This suggests that the mothers may have had psychiatric diagnoses already, which was not explored and could explain the findings through a genetic mechanism.

Interpretations & Limitations: The authors suggest 3 different types of explanations for their results. First, chemical substances might have caused a change in the neurodevelopment of the fetus, which increased the risk for schizophrenia later on. Secondly, there may have been an effect for some somatic or medical condition in the mother for which she took the pain relievers during pregnancy. Thirdly, there could be some unidentified factors (which could not be fully controlled in the analysis) that influenced intake of pain medicines by the mother and later risk for developing schizophrenia.

While it is interesting to learn that there maybe something unique about the second trimester that increases vulnerability to environmental factors and possible risk for schizophrenia, there are many reasons to be cautious about the findings. On top of the limitations with reduced power to detect results for certain analyses, the authors did not look at the effects of the mother drinking alcohol or using illegal drugs pregnancy, which could have influenced the outcome. They were also not able to address the question of taking pain medications for viral infection in the second trimester since only 15 mothers were exposed to both viral infection and took pain killers. Another limitation is that the data on prenatal exposure to medication that they used dated back to the early 1960s and some of the drugs used at that time are now obsolete in most countries. Much more research is needed to clarify the nature of the relationship between medications taken during pregnancy and later risk for schizophrenia.

This study was supported by: Sygekassernes Helsefond (Health Insurance Foundation) grant to H.J.S., grants HD-17655 and HD-20263 from the National Institute of Child Health and Human Development to J.M.R., grant DA-05056 from the National Institute on Drug Abuse to J.M.R., grant 9700093 from the Danish Research Council to E.L.M., and grant 1400/2-4-1997 from the Danish National Board of Health to E.L.M.

Click here to find this article on PubMed

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