Schizophrenia: An Inflammatory Disease That Can Be Treated With Aspirin?

Schizophrenia: An Inflammatory Disease That Can Be Treated With Aspirin?

Joined: April 1st, 2004, 4:56 pm

June 19th, 2010, 8:35 am #1

Quote
Like
Share

Joined: April 1st, 2004, 4:56 pm

June 19th, 2010, 8:49 am #2

Beneficial Antipsychotic Effects of Celecoxib Add-On Therapy Compared to Risperidone Alone in Schizophrenia
 

http://ajp.psychiatryonline.org/cgi/content/full/159/6/1029
<strong>Norbert Müller, M.D., Ph.D., Michael Riedel, M.D., Constanze Scheppach, Bernd Brandstätter, M.D., Safet Sokullu, M.D., Karin Krampe, M.D., Markus Ulmschneider, Rolf R. Engel, Ph.D., Hans-Jürgen Möller, M.D., and Markus J. Schwarz, M.D. </strong>
<a></a>

<table border="0" cellspacing="0" cellpadding="0" width="100%"><tr><td height="22" width="2%" align="left">
<img alt="" src="http://ajp.psychiatryonline.org/icons/toc/rarrow.gif" width="10" height="21">
</td><td bgcolor="#106848" width="98%">
  Abstract
</td></tr></table><table border="0" cellspacing="1" cellpadding="1" align="right"><tr><td> </td></tr><tr><td></td></tr></table> 
OBJECTIVE: Abnormalities in the immune system in schizophrenia</sup>have been described. However, important findings such as high<sup>levels of activating cytokines in the CSF and signs of CNS inflammation</sup>have been controversial. The authors conducted a trial of the<sup>new selective cyclooxygenase-2 inhibitor celecoxib, an immunomodulatory</sup>drug, in schizophrenic patients to evaluate its therapeutic<sup>effects. METHOD: In a prospective, double-blind evaluation,</sup>50 patients with an acute exacerbation of schizophrenia were<sup>randomly assigned to either risperidone plus celecoxib or risperidone</sup>plus placebo. After a washout period, 25 patients received 26<sup>mg/day of risperidone plus placebo and 25 received risperidone</sup>plus 400 mg/day of celecoxib for 5 weeks. The treatment effect<sup>was calculated by analysis of covariance. There were no significant</sup>differences between groups in age, sex, duration or severity<sup>of disease or psychopathology, or risperidone dose or plasma</sup>level. RESULTS: Over 5 weeks, both groups of patients showed<sup>significant improvement in scores on the Positive and Negative</sup>Syndrome Scale and on all subscales. However, the celecoxib<sup>group showed significantly greater improvement in the total</sup>score. CONCLUSIONS: Additional treatment with celecoxib has<sup>significant positive effects on the therapeutic action of risperidone</sup>with regard to total schizophrenia psychopathology. Moreover,<sup>the fact that treatment with an immunomodulatory drug showed</sup>beneficial effects on schizophrenia symptoms indicates that<sup>immune dysfunction in schizophrenia is not just an epiphenomenon</sup>but is related to the pathomechanism of the disorder. However,<sup>a nonimmunological therapeutic effect of celecoxib mediated</sup>by the N-methyl-D-aspartic acid receptor has to be taken into<sup>account.</sup>
<a></a>

<table border="0" cellspacing="0" cellpadding="0" width="100%"><tr><td height="22" width="2%" align="left">
<img alt="" src="http://ajp.psychiatryonline.org/icons/toc/rarrow.gif" width="10" height="21">
</td><td bgcolor="#106848" width="98%">
  Introduction
</td></tr></table><table border="0" cellspacing="1" cellpadding="1" align="right"><tr><td> </td></tr><tr><td></td></tr></table> 
Abnormalities in the immune function of schizophrenic patients<sup>
have been described over the last century (1). For instance,</sup>an inflammatory/immunological pathogenesis has been discussed<sup>for a subgroup of schizophrenic patients (24). Levels</sup>of activating cytokines, such as interleukin-1 (IL-1) and IL-2,<sup>in the CSF have been found to be higher than in comparison subjects</sup>(5, 6), and a high level of IL-2 in the CSF is a predictor of<sup>greater probability of a schizophrenic relapse (7).</sup>
Pharmacological down-regulation of activating cytokines in the<sup>
CNS due to anti-inflammatory therapy may have favorable effects</sup>on some schizophrenic patients. This view is supported by the<sup>fact that atypical antipsychotics have immunomodulatory properties</sup>(810) that may lead to a down-regulation of the immune<sup>response in the CNS.</sup>

With these findings, it seems useful to study the effects of<sup>
anti-inflammatory therapy by using an add-on agent together</sup>with a well-proven neuroleptic in schizophrenic patients.<sup>

Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor</sup>that enters the CNS well and has few adverse side effects. Risperidone<sup>was selected because it is an atypical neuroleptic with high</sup>efficacy for both positive and negative symptoms of schizophrenia,<sup>as well as an extensive history in the treatment of schizophrenia</sup>(11, 12).<sup>

<a></a>

<table border="0" cellspacing="0" cellpadding="0" width="100%"><tr><td height="22" width="2%" align="left">
<img alt="" src="http://ajp.psychiatryonline.org/icons/toc/rarrow.gif" width="10" height="21">
</td><td bgcolor="#106848" width="98%">
  Method
</td></tr></table><table border="0" cellspacing="1" cellpadding="1" align="right"><tr><td> </td></tr><tr><td></td></tr></table> 
[color=#4a4a4a" size="+1]Patients[/color]
This investigation was a prospective, double-blind study of</sup>parallel groups of patients with schizophrenia who were randomly<sup>assigned to treatment with either risperidone plus celecoxib</sup>or risperidone plus placebo. The study was approved by the local<sup>ethics committee of the medical faculty. Patients were included</sup>only after they had given their written informed consent to<sup>participate in the study.</sup>
Fifty schizophrenic patients were included in the study; 25<sup>
(11 women, 14 men) were randomly assigned to treatment with</sup>risperidone plus celecoxib, and 25 (14 women, 11 men) were assigned<sup>to risperidone plus placebo. The age range of the patients was</sup>18 to 65 years. The mean age was 35.9 years (SD=12.8) in the<sup>celecoxib group and 35.5 years (SD=13.6) in the placebo group.</sup>All patients had been hospitalized at the same facility because<sup>of an acute exacerbation of their schizophrenic psychosis. Sixteen</sup>of the patients had been hospitalized for the first time, eight<sup>in the celecoxib group and eight in the placebo group. Two independent</sup>specialists in psychiatry (M.R., B.B.) made the diagnosis of<sup>schizophrenia according to the criteria of DSM-IV. No patient</sup>fulfilled the criteria for treatment resistance.<sup>

After diagnosing and screening, patients who were receiving</sup>oral antipsychotic medication underwent a washout period of<sup>at least 48 hours. Twelve patients had been taking no neuroleptics</sup>for 3 months or more (five from the placebo group, seven from<sup>the celecoxib group). To calculate the mean length of the washout</sup>for these patients, a period of more than 3 months without neuroleptics<sup>was treated as equivalent to 3 months (90 days). The mean washout</sup>period was 29 days (SD=39) for the celecoxib group and 22 days<sup>(SD=34) for the placebo group. The range was 290 days</sup>in both groups.<sup>

Five patients were taking depot medication before admission</sup>to the hospital. The washout period for these patients had to<sup>be at least one injection interval. One of these patients was</sup>in the celecoxib group, and the washout period for that patient<sup>was two application intervals. For the four patients in the</sup>placebo group, the mean washout period was 1.6 intervals (SD=0.6).<sup>

During the washout period, the patients received benzodiazepines</sup>if necessary. Lorazepam was the drug of choice. Patients with<sup>agitation, anxiety, or sleep problems were also medicated with</sup>lorazepam during the study.<sup>

[color=#4a4a4a" size="+1]Procedure[/color]
The treatment period lasted 35 days (5 weeks). Assessment of</sup>psychopathology and other examinations were performed at weekly<sup>intervals. The dose of risperidone was flexible and ranged between</sup>2 and 6 mg/day, starting with 2 mg. The dose of celecoxib was<sup>200 mg in the morning and in the evening (400 mg/day). Patients</sup>in the placebo group received two identical capsules (morning<sup>and evening). The mean doses of risperidone in the celecoxib</sup>group and in the placebo group can be seen in Table 1.<sup>

<a></a>

<table border="1" cellspacing="0" cellpadding="20" width="100%"><tr valign="top"><td width="19%"><p align="center"><strong>View this table:</strong>
[in this window]
[in a new window]
 

</td><td bgcolor="#f3ede2" width="81%">
TABLE 1
</td></tr></table>

The psychopathology of the patients was assessed by three raters</sup>(K.K., C.S., S.S.), each of whom underwent a training program,<sup>using the Positive and Negative Syndrome Scale (13) and the</sup>Simpson-Angus Rating Scale for extrapyramidal side effects (14).<sup>The intraclass correlation (interrater reliability) was 0.92</sup>for both scales. At the start of the study, the mean total scores<sup>on the Positive and Negative Syndrome Scale of the groups receiving</sup>celecoxib and placebo, respectively, were 71.8 (SD=17.1) and<sup>75.4 (SD=12.9). Their mean scores for general psychopathology</sup>were 34.0 (SD=8.5) and 37.2 (SD=7.1). Their mean scores for<sup>positive symptoms were 19.0 (SD=5.9) and 17.2 (SD=4.6), and</sup>their mean scores for negative symptoms were 18.7 (SD=6.3) and<sup>21.1 (SD=5.5). At baseline, no significant difference between</sup>the groups in the total score or any of the subscale scores<sup>could be found.</sup>
Biperiden was made available for the side effects of the antipsychotic<sup>
medication. For the treatment of agitation or anxiety, benzodiazepines</sup>were available. Lorazepam was mostly used. For comparison, the<sup>doses of benzodiazepines were calculated as diazepam equivalents.</sup>

In order to exclude the chance that any differences in treatment<sup>
response between the groups might be due to noncompliance during</sup>risperidone therapy or to differences in risperidone metabolism,<sup>risperidone plasma levels and plasma levels of 9-hydroxyrisperidone</sup>were monitored during the study.<sup>

[color=#4a4a4a" size="+1]Analysis[/color]
The statistics were performed according to the criterion of</sup>last observation carried forward; i.e., the last scores of patients<sup>who dropped out before the end of the study were carried forward</sup>to all subsequent observation days.<sup>

Since the difference between groups in the main outcome variable</sup>(total score on the Positive and Negative Syndrome Scale) at<sup>baseline favored the experimental group, analysis of covariance</sup>was used as the primary inferential statistic. A randomized<sup>block design was used with the baseline value on the Positive</sup>and Negative Syndrome Scale as covariate, the experimental and<sup>control groups as a between-subjects factor (group), and the</sup>five weekly measurements during treatment as the within-subjects<sup>factor (time). This was done for the Positive and Negative Syndrome</sup>Scale total scale and the positive, negative, and general psychopathology<sup>subscales. The degrees of freedom for the within-subjects comparisons</sup>were corrected for deviance from sphericity.<sup>

<a></a>

<table border="0" cellspacing="0" cellpadding="0" width="100%"><tr><td height="22" width="2%" align="left">
<img alt="" src="http://ajp.psychiatryonline.org/icons/toc/rarrow.gif" width="10" height="21">
</td><td bgcolor="#106848" width="98%">
  Results
</td></tr></table><table border="0" cellspacing="1" cellpadding="1" align="right"><tr><td> </td></tr><tr><td></td></tr></table> 
Four patients in the celecoxib group and three patients in the</sup>placebo group dropped out before the end of the study. The dropouts<sup>from the placebo group were aged 29, 31, and 63 years (two women,</sup>one man), and they dropped out at days 7, 15, and 17. The reasons<sup>for dropping out were acute stomachache, worsening of psychosis,</sup>and severe akathisia. The dropouts from the celecoxib group<sup>were aged 23, 26, 45, and 61 years (one woman, three men), and</sup>they dropped out at days 5, 9, and 17. The reasons for dropping<sup>out of three patients were edema of the leg, lack of improvement,</sup>and ECG change. One patient improved very rapidly and moved<sup>to another town at day 18.</sup>
Both groups showed a significant improvement in psychopathology<sup>
over the 5 weeks of treatment. As expected, both treatments</sup>reduced the total score on the Positive and Negative Syndrome<sup>Scale gradually over the 5 weeks; univariate analysis of the</sup>within-subjects factor, time, indicated a significant effect<sup>(Greenhouse-Geisser-corrected F=3.33, df=2, 90, p=0.04). This</sup>effect of time resulted mainly from reductions in the scores<sup>on the positive symptom subscale (F=4.68, df=2.6, 122, p=0.006)</sup>and on the general psychopathology subscale (F=4.47, df=2.4,<sup>111, p=0.01), whereas negative symptoms were not reduced significantly</sup>(F=0.74, df=1.9, 89, p=0.47). The effects of risperidone treatment,<sup>however, were not the focus of our study.</sup>

The celecoxib add-on therapy had a significant effect on the<sup>
mean improvement in total Positive and Negative Syndrome Scale</sup>score, as indicated by the effect of group, the between-subjects<sup>factor (F=3.80, df=1, 47, p=0.05). The difference between the</sup>two treatment groups was not homogeneous across time (multivariate<sup>group-by-time interaction: F=3.91, df=4, 44, p=0.008). The main</sup>effects of celecoxib were seen in the middle of the treatment<sup>period (quadratic interaction component: F=12.50, df=1, 47,</sup>p=0.001). In simple post hoc t tests the difference between<sup>the two treatment groups was significant from week 2 to week</sup>4 (week 2: t=2.06, df=48, p=0.05; week 3: t=2.64, df=48, p=0.01;<sup>week 4: t=2.54, df=48, p=0.01). There was no significant effect</sup>of group (celecoxib or placebo) on any of the subscales (positive<sup>symptoms: F=1.74, df=1, 47, p=0.19; negative symptoms: F=2.82,</sup>df=1, 47, p=0.10; general psychopathology: F=3.19, df=1, 47,<sup>p=0.08). The quadratic trend in the group-by-time interaction,</sup>however, was present for all subscales (positive symptoms: F=4.77,<sup>df=1, 47, p=0.03; negative symptoms: F=8.86, df=1, 47, p=0.005;</sup>general psychopathology: F=6.16, df=1, 47, p=0.02). The celecoxib<sup>add-on treatment did result in earlier improvement in all subscale</sup>scores (Figure 1).<sup>

<a></a>

<table border="1" cellspacing="0" cellpadding="20" width="100%"><tr valign="top"><td width="28%"><p align="center"><img border="0" alt="" src="http://ajp.psychiatryonline.org/content/vol159/issue6/images/small/K521F1.gif" width="140" height="200">
<strong>View larger version</strong> (37K):
[in this window]
[in a new window]
 

</td><td bgcolor="#f3ede2" width="72%">
Figure 1. Scores on the Positive and Negative Syndrome Scale and Its Subscales Over 5 Weeks for Patients With Schizophrenia Treated With Risperidone Plus Celecoxib (N=25) or Risperidone Plus Placebo (N=25)


</td></tr></table>

The mean daily dose of risperidone can be seen in Table 1. No</sup>difference was found at any of the time points; i.e., differences<sup>in the response to therapy were not due to different risperidone</sup>doses. In addition, they were not due to differences in the<sup>plasma level of risperidone or its only active metabolite, 9-hydroxyrisperidone,</sup>as can be seen from Table 2.<sup>
<a></a>

<table border="1" cellspacing="0" cellpadding="20" width="100%"><tr valign="top"><td width="19%"><p align="center"><strong>View this table:</strong>
[in this window]
[in a new window]
 

</td><td bgcolor="#f3ede2" width="81%">
TABLE 2
</td></tr></table>

With respect to the extrapyramidal side effects, no statistically</sup>significant difference could be found in scores on the Simpson-Angus<sup>Rating Scale. The use of biperiden was calculated as mean daily</sup>dose for each week. No statistically significant difference<sup>could be observed. The use of benzodiazepines was lower in the</sup>celecoxib group than in the placebo group, but the difference<sup>was not statistically significant (Figure 2).</sup>
<a></a>

<table border="1" cellspacing="0" cellpadding="20" width="100%"><tr valign="top"><td width="28%"><p align="center"><img border="0" alt="" src="http://ajp.psychiatryonline.org/content/vol159/issue6/images/small/K521F2.gif" width="169" height="200">
<strong>View larger version</strong> (31K):
[in this window]
[in a new window]
 

</td><td bgcolor="#f3ede2" width="72%">
Figure 2. Doses of Biperiden and Benzodiazepines Over 5 Weeks for Patients With Schizophrenia Treated With Risperidone Plus Celecoxib (N=25) or Risperidone Plus Placebo (N=25)


</td></tr></table>

Side effects that have been attributed to the administration<sup>
of celecoxib, especially gastrointestinal problems, were not</sup>observed. One patient who was receiving risperidone and placebo<sup>dropped out of the study because of gastrointestinal problems.</sup>The reasons leading to study dropout in the celecoxib group<sup>are described in the literature as side effects of risperidone</sup>(edema, changes in the ECG). However, further studies are needed<sup>to evaluate whether additive effects may play a role. In general,</sup>however, the dropout rate was low in both groups; for celecoxib<sup>it was 16% and for placebo it was 12%.</sup>
<a></a>

<table border="0" cellspacing="0" cellpadding="0" width="100%"><tr><td height="22" width="2%" align="left">
<img alt="" src="http://ajp.psychiatryonline.org/icons/toc/rarrow.gif" width="10" height="21">
</td><td bgcolor="#106848" width="98%">
  Discussion
</td></tr></table><table border="0" cellspacing="1" cellpadding="1" align="right"><tr><td> </td></tr><tr><td></td></tr></table> 
Risperidone is a well-established atypical antipsychotic with<sup>
proven efficacy in schizophrenia (11, 12). As expected, both</sup>groups of schizophrenic patients showed significant improvement<sup>on the total Positive and Negative Syndrome Scale and on most</sup>subscales during the 5 weeks of treatment with risperidone.<sup>
In agreement with our hypothesis, the celecoxib add-on therapy</sup>group had significantly greater improvement in the Positive<sup>and Negative Syndrome Scale total score. The largest improvements</sup>were seen between weeks 2 and 4. In practice, this means an<sup>earlier response to treatment with the add-on therapy. The acceleration</sup>of response could be seen in similar ways in all subscales.<sup>These results show that the additional treatment with celecoxib</sup>has significant, positive effects on the psychopathology of<sup>schizophrenia.</sup>

The therapeutic benefit in the group receiving risperidone plus<sup>
celecoxib could not be attributed to the dose or to the plasma</sup>level of risperidone or its active metabolite 9-hydroxyrisperidone.<sup>Clinical characteristics of the schizophrenic patients, such</sup>as sex and duration or severity of the disorder, did not differ<sup>between groups and cannot explain differences in the therapeutic</sup>outcome.<sup>

Extrapyramidal side effects measured by the Simpson-Angus Rating</sup>Scale showed no significant statistical difference. The use<sup>of biperiden was greater in the group receiving risperidone</sup>plus placebo during the first 2 weeks, but the difference was<sup>not statistically significant. The need for lower doses of biperiden</sup>during the first weeks of the trial is in accordance with a<sup>neuroprotective effect of celecoxib, which is discussed in the</sup>literature (15). Therapy with 400 mg/day of celecoxib was well<sup>tolerated, and no clinically important side effects were observed.</sup>

The therapeutic benefit of the combined therapy has to be attributed<sup>
to effects of celecoxib. The effects of celecoxib in the CNS</sup>are not yet clear. There is no doubt that activation of COX-2<sup>mediates inflammation and that COX-2 is expressed in brain tissue.</sup>COX-2 can be activated by cytokines, such as IL-2, IL-6, and<sup>IL-10, and cytokine-activated COX-2 expression mediates further</sup>inflammation. It is reported that CSF levels of IL-2 and sIL-2R<sup>(6, 7), soluble IL-6 receptors that are a functional part of</sup>the IL-6 system (16), and IL-10 (17) are high in schizophrenic<sup>patients. The high levels of cytokines in the CNS compartment</sup>may be accompanied by increased COX-2 expression. We hypothesize<sup>that celecoxib down-regulates the cytokine-induced CNS COX-2</sup>activation.<sup>

Moreover, COX-2 inhibition seems to regulate the expression</sup>of adhesion molecules (18). Regulation of adhesion molecules<sup>is impaired in schizophrenia, possibly leading to imbalance</sup>and a lack of communication between the peripheral and the CNS<sup>immune systems (1921). The effects of celecoxib in schizophrenia</sup>may also be related to intercellular adhesion molecule-1 and<sup>vascular cell adhesion molecule-1, especially the effects on</sup>negative symptoms (22, 23).<sup>

There may be a special subgroup of patients who benefit from</sup>celecoxib more than others, since even an onset of psychotic<sup>symptoms during celecoxib therapy has been described (24).</sup>

Several factors that may play a role in the effect of celecoxib<sup>
in schizophrenia could not be considered because research and</sup>experience are lacking. First, with regard to the dose of celecoxib,<sup>the therapeutic recommendations vary between 100 and 200 mg/day</sup>in the treatment of acute rheumatoid arthritis and 800 mg/day<sup>in familial polyposis. Since we know of no data for celecoxib</sup>treatment of CNS disorders, we chose a medium dose. Lower or<sup>higher doses may have been more beneficial.</sup>

Second, it is known that celecoxib penetrates the CNS (25).<sup>
Exact basic human data about its pharmacokinetics, pharmacodynamics,</sup>and degree of CNS penetration are lacking. Those data would<sup>be necessary for better estimation of the dose needed to treat</sup>CNS disorders.<sup>

Third, the duration of the study was planned according to clinical</sup>considerations based on previous treatment studies with typical<sup>and atypical antipsychotics. However, it would be interesting</sup>to study the effects of celecoxib in schizophrenia over a longer<sup>treatment period. Longer treatment studies are especially required</sup>to investigate effects on negative symptoms. Substances acting<sup>according to other therapeutic principlese.g., anti-inflammatory</sup>mechanisms in the CNSmay affect the duration of a therapeutic<sup>trial differently. Thus, the ultimate therapeutic benefit of</sup>adjunctive celecoxib may require much more optimization of dose,<sup>duration, etc.</sup>

From a scientific viewpoint, the therapeutic effects of celecoxib<sup>
without an additional neuroleptic drug would be more interesting.</sup>However, since neuroleptics are effective in antipsychotic treatment,<sup>ethics committees would not approve a study with a COX-2 inhibitor</sup>as the only drug for acutely ill schizophrenic patients.<sup>

This study was planned according to the psychoneuroimmunological</sup>hypothesis that a lipophilic anti-inflammatory substance may<sup>lead to therapeutic benefits in schizophrenia. The result is</sup>one more indication that immune dysfunction in schizophrenia<sup>may be related to the pathomechanism of schizophrenia and is</sup>not just an epiphenomenon.<sup>

The therapeutic effects of COX-2 inhibition in other neuropsychiatric</sup>disorders, such as Alzheimers disease (26) and cerebral<sup>ischemia (27), have also been discussed. The possible specific</sup>action in schizophrenia has to be elucidated in further studies.<sup>It has to be taken into account that the therapeutic effect</sup>of celecoxib is mediated not only by immune mechanisms but by<sup>glutamatergic mechanisms as well. COX-2 is expressed on neurons</sup>(28) in structures critically involved in the pathology of schizophrenia,<sup>such as the hippocampus and amygdala (29, 30), and it is functionally</sup>related to glutamatergic receptors (31). Different effects of<sup>COX-2 inhibitors on glutamatergic neurotransmission have been</sup>shown; i.e., the effects of COX-2 mediated by kainate receptors<sup>were observed to be activated (32), whereas effects mediated</sup>by the N-methyl-D-aspartic acid (NMDA) receptor were inhibited<sup>(28). This may be important for the celecoxib effects in schizophrenia</sup>because there is evidence that an overactivation of NMDA receptors<sup>is involved in the pathogenesis of schizophrenia (33).</sup>

Regardless of the mechanism(s) involved, short-term add-on treatment<sup>
with celecoxib appears to have a beneficial effect on schizophrenic</sup>psychopathology.<sup>

</sup>

<a></a>

<table border="0" cellspacing="0" cellpadding="0" width="100%"><tr><td height="22" width="2%" align="left">
<img alt="" src="http://ajp.psychiatryonline.org/icons/toc/rarrow.gif" width="10" height="21">
</td><td bgcolor="#106848" width="98%">
  Footnotes
</td></tr></table> 
<a></a>Received March 9, 2001; revisions received Aug. 14 and Nov.<sup>
26, 2001; accepted Dec. 18, 2001. From the Psychiatric and Psychotherapeutic</sup>Hospital, Ludwig Maximilians University, Munich. Address reprint<sup>requests to Dr. Müller, Psychiatrische Klinik der Ludwig-Maximilians-Universität,</sup>Nussbaumstrasse 7, 80336 München, Germany; <span>[url=mailto:nmueller@psy.med.uni-muenchen.de]nmueller@psy.med.uni-muenchen.de[/url]</span><sup>(e-mail). Supported by a grant from the Theodore and Vada Stanley</sup>Foundation Research Programs. The study is dedicated to the<sup>75th birthday of Professor Hanns Hippius.<sup></sup>
<a></a>

<table border="0" cellspacing="0" cellpadding="0" width="100%"><tr><td height="22" width="2%" align="left">
<img alt="" src="http://ajp.psychiatryonline.org/icons/toc/rarrow.gif" width="10" height="21">
</td><td bgcolor="#106848" width="98%">
  References
</td></tr></table><table border="0" cellspacing="1" cellpadding="1" align="right"><tr><td> </td></tr><tr><td></td></tr></table> 
<a></a>Rapaport MH, Müller N: Immunological states associated with schizophrenia, in Psychoneuroimmunology, 3rd ed, vol 2. Edited by Ader R, Felten DL, Cohen N. San Diego, Calif, Academic Press, 2001, pp 373-382 Yolken RH, Torrey EF: Viruses, schizophrenia, and bipolar disorder. Clin Microbiol Rev 1995; 8:131-145[Abstract/Free Full Text] Körschenhausen D, Hampel H, Ackenheil M, Penning R, Müller N: Fibrin degradation products in post mortem brain tissue of schizophrenics: a possible marker for underlying inflammatory processes. Schizophr Res 1996; 19:103-109[CrossRef][Medline] Müller N, Ackenheil M: Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 1998; 22:1-33[CrossRef][Medline] Sirota P, Schild K, Elizur A, Djaldetti M, Fishman P: Increased interleukin-1 and interleukin-3 like activity in schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 1995; 19:75-83[Medline] Licinio J, Seibyl JP, Altemus M, Charney DS, Krystal JH: Elevated CSF levels of interleukin-2 in neuroleptic-free schizophrenic patients. Am J Psychiatry 1993; 150:1408-1410[Abstract/Free Full Text] McAllister CG, van Kammen DP, Rehn TJ, Miller AL, Gurklis J, Kelley ME, Yao J, Peters JL: Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status. Am J Psychiatry 1995; 152:1291-1297[Abstract/Free Full Text] Müller N, Empel M, Riedel M, Schwarz MJ, Ackenheil M: Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia. Eur Arch Psychiatry Clin Neurosci 1997; 247:308-313[Medline] Lin A, Kenis G, Bignotti S, Tura GJB, De Jong R, Bosmans E, Pioli R, Altamura C, Scharpé S, Maes M: The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophr Res 1998; 32:9-15[CrossRef][Medline] Maes M, Bosmans E, Calabrese J, Smith R, Meltzer HY: Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood-stabilizers. J Psychiatr Res 1995; 29:141-152[CrossRef][Medline] Marder SR, Meibach RC: Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994; 151:825-835[Abstract/Free Full Text] Möller HJ, Gagiano DA, Addington CE, von Knorring L, Torres-Plank JL, Gaussares C: Long-term treatment of schizophrenia with risperidone: an open-label, multicenter study of 386 patients. Int Clin Psychopharmacol 1998; 13:99-106[Medline] Kay SR, Fiszbein A, Opler LA: The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13:261-276 Simpson GM, Angus JWS: A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970; 212:11-19[Medline] Klegeris A, Walker DG, McGeer PL: Neurotoxicity of human THP-1 monocytic cells towards neuron-like cells is reduced by non-steroidal antiinflammatory drugs (NSAIDs). Neuropharmacology 1999; 38:1017-1025[CrossRef][Medline] Müller N, Dobmeier P, Empel M, Riedel M, Schwarz M, Ackenheil M: Soluble IL-6 receptors in the serum and cerebrospinal fluid of paranoid schizophrenic patients. Eur Psychiatry 1997; 12:294-299[Medline] van Kammen DP, McAllister-Sistilli CG, Kelley ME: Relationship between immune and behavioral measures in schizophrenia, in Current Update in Psychoimmunology. Edited by Wieselmann G. New York, Springer, 1997, pp 51-55 Bishop-Bailey D, Burke-Gaffney A, Hellewell PG, Pepper JR, Mitchell JA: Cyclo-oxygenase-2 regulates inducible ICAM-1 and VCAM-1 expression in human vascular smooth muscle cells. Biochem Biophys Res Commun 1998; 249:44-47[CrossRef][Medline] Schwarz MJ, Riedel M, Ackenheil M, Müller N: Decreased levels of soluble intercellular adhesion molecule-1 (sICAM-1) in unmedicated and medicated schizophrenic patients. Biol Psychiatry 2000; 47:29-33[CrossRef][Medline] Müller N, Riedel M, Hadjamu M, Schwarz MJ, Ackenheil M, Gruber R: Increase in expression of adhesion molecule receptors on T helper cells during antipsychotic treatment and relationship to blood-brain barrier permeability in schizophrenia. Am J Psychiatry 1999; 156:634-636[Abstract/Free Full Text] Schwarz MJ, Ackenheil M, Riedel M, Müller N: Blood-CSF-barrier impairment as indicator for an immune process in schizophrenia. Neurosci Lett 1998; 253:201-203[Medline] Schwarz MJ, Riedel M, Gruber R, Ackenheil M, Müller N: Levels of soluble adhesion molecules in schizophrenia: relation to psychopathology, in Psychiatry, Psychoneuroimmunology, and Viruses. Edited by Müller N. New York, Springer, 1999, pp 121-130 Müller N, Ackenheil M: Immunoglobulin and albumin contents of cerebrospinal fluid in schizophrenic patients: the relationship to negative symptomatology. Schizophr Res 1995; 14:223-228[CrossRef][Medline] Lantz MS, Giambanco V: Acute onset of auditory hallucinations after initiation of celecoxib therapy (letter). Am J Psychiatry 2000; 157:1022-1023[Free Full Text] Hubbard RC, Koepp RJ, Yu S, Talwalker S, Geis GS, Wiesenhutter CW, Makarowski WS, Paulus HA: SC-58635 (celecoxib), a novel COX-2 selective inhibitor, is effective as a treatment for osteoarthritis in a short-term pilot study (abstract). Arthritis Rheum 1996; 39(suppl 9):S123 McGeer PL: Cyclo-oxygenase-2 inhibitors: rationale and therapeutic potential for Alzheimers disease. Drugs Aging 2000; 1:1-11 Nogawa S, Zhang F, Ross ME, Iadecola C: Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 1997; 17:2746-2755[Abstract/Free Full Text] Hewett SJ, Uliasz TF, Vidwans AS, Hewett JA: Cyclooxygenase-2 contributes to N-methyl-D-aspartate-mediated neural cell death in primary cortical cell culture. J Pharmacol Exp Ther 2000; 293:417-425[Abstract/Free Full Text] Yamagata K, Andreasson KI, Kaufmann WI, Barnes CA, Worley PF: Expression of mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 1993; 11:371-386[CrossRef][Medline] Breder CD, Saper CB: Expression of inducible cyclooxygenase mRNA in the mouse brain after systemic administration of bacterial lipopolysaccharide. Brain Res 1996; 713:64-69[CrossRef][Medline] Yermakova A, OBanion MK: Cyclooxygenases in the central nervous system: implications for treatment of neurological disorders. Curr Pharm Des 2000; 6:1755-1776[CrossRef][Medline] Baik EJ, Kim EJ, Lee SH, Moon C: Cyclooxygenase-2 selective inhibitors aggravate kainic acid induced seizure and neuronal cell death in the hippocampus. Brain Res 1999; 843:118-129[CrossRef][Medline] Carlsson A: Schizophrenie und Neurotransmitter-Störungen: neue Perspektiven und therapeutische Ansätze, in Moderne Konzepte zu Diagnostik, Pathogenese und Therapie der Schizophrenie. Edited by Möller HJ, Müller N. New York, Springer-Verlag, 1998, pp 93-116
Quote
Like
Share

Joined: April 19th, 2005, 7:01 pm

June 21st, 2010, 8:54 pm #3

Quote
Like
Share

Joined: April 19th, 2005, 7:01 pm

June 21st, 2010, 8:57 pm #4

Praps we should be having a go at those greedy GREEDY ass*oles who don't give a TOSS about the people their greed kills.
Quote
Like
Share

Joined: April 19th, 2005, 7:01 pm

June 22nd, 2010, 6:46 pm #5

Simple - the only thing that was wrong will show to be the environment, a simple inflamation, kids coping with real problems, ie mental "illness" is just a reaction to life, or to health.

BUT in the meantime, the drug companies - aka the pharmaceutical companies - have damaged and killed hundreds of thousands of people.

Mostly because the people who should THINK...DON'T THINK now when they could be making a difference.

 

DOCTORS SHOULD BE SAVING LIVES.  But no, they're so up their own arses and their own self interest as per what benefits they can get from helping to deceive the people that they're helping drug makers to KILL PEOPLE.  Little people (children), Big people, (moms, dads). So Doctors finished being the people they were a couple of centuries ago, and now they're simply and arrogantly into money.

What a horrible horrible time this early 21st century is.   Its bound to change sometime, but it isn't changing now.
Quote
Like
Share

Joined: April 19th, 2005, 7:01 pm

June 22nd, 2010, 6:56 pm #6


downwards when you realise just WHAT YOUR DOCTOR EITHER CANNOT BE BOTHERED TO LEARN  OR IS JUST NOT BRIGHT ENOUGH AND SO INCAPABLE OF LEARNING.

 

IQ levels?  Watch out docs, it seems your patients, once they've cottoned onto your fakery, are MOSTLY brighter than you are.  End of the 'medical profession' and its "dear DOCTOR" status.  The start of "Hey, MISTER/MISSES" Jones... what do you feel about this or that..."

You docs are no brighter than the average patient you see.  You just had (but have f*cked up) your chance at pretending you were.

 

I'll probably delete this message sometime soon.
Last edited by SSRIAdmin on June 22nd, 2010, 7:00 pm, edited 1 time in total.
Quote
Like
Share

Joined: April 19th, 2005, 7:01 pm

June 22nd, 2010, 7:07 pm #7


well, there's the rub as Shakespeare would have said.

Just like in any other discipline, there are the few greats, the few nearly greats, and the others, the average.

In art, literature, music and the rest, it doesn't matter.

In MEDICINE of EVERY OR ANY KIND, everything matters.  Because it needs the GREATS to recognise what to avoid, what kills, and there are simply so few of those that the AVERAGE degree graduates are causing global harm, lots of disability and lots of deaths because those very poor but wealthy educated people with a degree in medicine or psychiatry just don't have the intelligence to do something about it.

The average, which by definition of 'average' are the most common graduates, seem to be so little interested in medicine, and much more  interested in  Sugar Daddies - the drug manufacturers that can give them the career that only the 'greats' actually DESERVED but are unlikely to get - that they become dead happy/ dead easy to swap ethics for shares, gifts, holidays, a push up the ladder of fame, money, high positions.  And the rest.

How pathetic is that?
Last edited by SSRIAdmin on June 22nd, 2010, 7:24 pm, edited 1 time in total.
Quote
Like
Share