Amisulpride: Is There a Treatment for Negative Symptoms in Schizophrenia Patients?

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1 Amisulpride: Is There a Treatment for Negative Symptoms in Schizophrenia Patients? by Jitschak Q. Storosum, Andre J.A. Elferink, Barbara J. van Zwieten, Roel van Strik, Witte J.Q. Hoogendijk, and Andre W. Broekmans Abstract In this article we report on a meta-analysis of the published studies of amisulpride conducted in order to demonstrate efficacy on primary negative symptoms in schizophrenia. Four placebo-controlled studies were conducted in patients with predominantly negative symptoms. In all studies a significant improvement was observed on the Scale for the Assessment of Negative Symptoms (SANS) in the amisulpride groups ( mg daily) as compared to placebo. The improvement on the SANS was not accompanied by a simultaneous improvement on the Scale for the Assessment of Positive Symptoms (SAPS) or a decrease in extrapyramidal symptoms (EPS) in three of the four studies, indicating a genuine effect on primary negative symptoms. The overall analysis shows that the improvement on the SANS was accompanied by a small simultaneous improvement on the SAPS. Moreover, in the studies where depressive symptoms were measured, a significant improvement was also shown in favor of amisulpride. However, as the SAPS and the Montgomery Asberg Depression Rating Scale (MADRS) baseline scores were rather low, the improvement on both scales in favor of amisulpride is probably not responsible for the improvement on the SANS. A positive correlation was found between the severity on the mean SANS score at baseline and mean improvement at endpoint, and a surprisingly high success rate was observed in the placebo groups, indicating either that primary negative symptoms are not as persistent as had previously been thought, or that the concept of primary negative symptoms should be reconsidered. Probably amisulpride is efficacious on these nonenduring primary negative symptoms. Keywords: Negative symptoms, amisulpride, placebo, methodology. Schizophrenia Bulletin, 28(2):93-20,2002. Kraepelin (97) regarded schizophrenia primarily as a defect state with a deteriorative course. Although there has been steady interest in (the treatment of) negative symptoms (Strauss et al. 974; Carpenter et al. 985), gradually more emphasis has been put on positive symptoms as pathognomonic of the disorder and even prerequisites for its diagnosis (Kay and Opler 987). The significance attached to positive symptoms is evidenced, for example, in the diagnostic criteria for schizophrenia as put forth by Schneider (959), Feighner et al. (972), the RDC (977), and DSM-III and DSM-III-R (APA 980, 987). The emphasis on positive symptoms has led to the view that in the treatment of schizophrenia, two stages can be distinguished: () the treatment of acute exacerbation, and (2) the maintenance phase, which strives to prevent relapse or recurrence. Dopamine receptor blocking compounds, the classic antipsychotics, have been shown to be efficacious in both stages. In the past decade interest in negative symptoms has re-emerged, and since DSM-IV (APA 994) three negative symptomsaffective flattening, alogia, and avolitionare now included in the definition of schizophrenia. Carpenter et al. (988) made a distinction between primary and secondary negative symptoms. Primary negative symptoms correspond to a deficit state, while secondary negative symptoms may be due to many reasons, such as psychotic turmoil, EPS, depression, or environmental understimulation. This renewed interest in negative symptoms has led to a greater awareness of the treatment of such symptoms. Although primary negative symptoms were always considered as enduring traits (Carpenter et al. 988) and not responsive to classic antipsychotic treatment (Crow 985), amisulpride, a substituted benzamide with high affinity for dopamine (D 2 /D 3 ) receptors (Perrault et al. 997), is alleged to be effective on primary negative symptoms. At low doses it Send reprint requests to Dr. J.G. Storosum, Medicines Evaluation Board of the Netherlands, Kalvermarkt 53, PO-BOX 6229, 2500 BE Den Haag, The Netherlands; J.G.Storosum@amc.uva.nl. 93

2 Schizophrenia Bulletin, Vol. 28, No. 2, 2002 J.G. Storosum et al. shows selective blockade of presynaptic dopamine autoreceptors and increased release of dopamine (Perrault et al. 997; Schoemaker et al. 997). In animal models lowdose amisulpride did not result in catalepsy and led to prohedonic behavior in rats that could be predictive for efficacy on negative symptoms (Scatton et al. 997). At high doses, amisulpride shows merely postsynaptic binding at limbic dopamine receptors and animal behavior that could be predictive for efficacy on positive symptoms (Perrault et al. 997). However, the clinical relevance of these findings is unclear. This article reviews the clinical studies that have been conducted with amisulpride in the treatment of negative symptoms and discusses the methodology and the results of these studies. Method Study Identification. We searched the Medline data base (from 966 through July 999) for literature with the keywords "amisulpride" and "controlled study." The search was restricted to studies in patients with predominantly negative symptoms. Data Analysis. Confidence intervals (95 percent) were computed for differences between amisulpride and placebo, with respect to mean changes of total scores for the primary efficacy outcome measurements from baseline, based on the data presented in the papers. Standard errors of changes in mean scores were estimated from corresponding standard deviation (SD) values, either as published (Danion et al. 999) or as derived from relevant information about variability in the paper (Paillere- Martinot et al. 995; Loo et al. 997). However, such information was not available in Boyer et al. (995). Therefore we decided to use the average SD as an approximate estimate of the SD value for that study. This seemed justified, because two of the authors were also involved in the paper by Paillere-Martinot et al. (995), which implies similar circumstances. The resulting SD values turned out to be fairly homogeneous with regard to the SANS, the average being With regard to the SAPS we used a similar approach, although the SD values were more heterogeneous than for the SANS scores. The overall estimate and confidence intervals were based on a fixed model, weighed for variance differences between the studies. Results Four controlled studies were identified (Boyer et al. 995; Paillere-Martinot et al. 995; Loo et al. 997; Danion et al. 999). In all studies schizophrenia patients with predominantly negative symptoms were included. In the study of Paillere-Martinot et al. (995), six patients who met the criteria for schizotypal personality disorder were also included. With regard to exclusion criteria, in the study of Paillere-Martinot et al. (995) patients with organic brain disorder, somatic disease, or alcohol or drug abuse and patients with prominent positive symptoms or depression were excluded. Patients fulfilling criteria for positive schizophrenia were excluded in the study of Boyer et al. (995); and in the study of Loo et al. (997), patients presenting other major DSM-III-R diagnosis, risk of suicide, alcohol or drug abuse, or Parkinson's disease or any other severe somatic disease were excluded. In the study of Danion et al. (999), patients with other DSM-III-R criteria were not excluded. All studies were placebo controlled and used different types of the SANS (Andreasen 9846) and the SAPS (Andreasen 984a) as primary outcome measurement. Table contains an overview of these four placebo-controlled studies. The duration of the double-blind period varied from 6 weeks to 26 weeks. The dose of amisulpride ranged from 50 mg to 300 mg. The severity scores at baseline on the SANS and SAPS indicated marked negative symptoms and rather low positive symptoms. Dropout percentages ranged from 2 percent to 68 percent, the highest appearing in the study of 26 weeks. There was a tendency for more dropouts in the placebo groups than in the amisulpride groups. The main reason for dropout was the occurrence of exacerbation or lack of efficacy, or both (table 2). Figure shows the differences between active treatment and placebo in mean change from baseline on the SANS and the SAPS. In the study of Danion et al. (999), the improvement in the amisulpride group on the SANS was accompanied by an improvement on the SAPS. In the other three studies the beneficial effect of amisulpride on the SANS was not accompanied by simultaneous improvement on the SAPS. The overall analysis shows that the improvement on the SANS was accompanied by a small simultaneous improvement on the SAPS. The studies found a positive correlation between the mean SANS baseline scores and the mean improvement on the SANS at endpoint (Pearson correlation coefficient = 0.735; p = 0.05, n = 0 treatment arms). Table 3 shows the SANS subscale effects. On all subscales of the SANS, amisulpride was superior to placebo, and in most cases the difference was statistically significant. The studies differed considerably in the assessment of EPS. In the study of Boyer et al. (995), the score on the Extrapyramidal Symptom Scale was low in all treatment groups at baseline. At the end of the study there was 94

3 Amisulpride Schizophrenia Bulletin, Vol. 28, No. 2, 2002 Table. Characteristics of the four placebo-controlled studies conducted to demonstrate efficacy on negative symptoms Source Patients included Other inclusion criteria Washout Study duration Paillere- Martino etal. (995) DSM-III-R diagnosis of schizophrenia: disorganized and undifferentiated or schizotypal personality disorder Young age, SANS: mean items rating of 3 in at least two subscales, short disease course, neuroleptic naive condition or treatment < mo No (drug-free patients) or lifetime drug treatment < mo 6 wks Boyer et al. (995) DSM-III-R diagnosis of schizophrenia: disorganized, catatonic, undifferentiated, or residual Andreasen criteria for negative schizophrenia* SANS > 75 points SAPS < 60 points 6wks, 2 wks if they had received depot medication 6 wks Loo et al. (997) DSM-III-R diagnosis of schizophrenia: disorganized or residual type, subchronic or chronic Andreasen criteria for negative schizophrenia* SANS > 60 points No 26 wks Danion et al. (999) DSM-III-R diagnosis of schizophrenia: residual type or < 20 yrs SAPS < 50 points 4 wks Note.SANS = Scale for the Assessment of Negative Symptoms; SAPS = Scale for the Assessment of Positive Symptoms. 2 wks * The presence of at least two of the following symptoms with severe/marked intensity: alogia, affective blunting, anhedonia, asociality, avolition/apathy, attentional impairment. Table 2. Patients randomized, analyzed, and early terminated Source Paillere- Martinot etal. (995) Boyer et al. (995) Treatments Amisulpride 50 mg Amisulpride 00 mg Amisulpride 300 mg Randomized 4 3 CO CO CO n Analyzed Exacerbation 4 LOE Early Terminated Worsening 2 ADEs Other reason Loo et al. (997) Amisulpride 00 mg Danion etal. (999) Amisulpride 50 mg Amisulpride 00 mg Note.ADEs = adverse events; LOE = loss of efficacy. a small decrease in all treatment groups without statistically significant differences between groups. In the study of Paillere-Martinot et al. (995), EPS data were rated according to the items from the somatic subscale of the Association for Methodology and Documentation in Psychiatry (AMDP) system. Sixty-five percent of the patients had some extrapyramidal abnormalities before treatment. At the end of this study more patients in the amisulpride group had EPS than patients on placebo. In the study of Loo et al. (997), EPS scores on the Webster scale were rated as mild at the start of the study. Seven out of 72 patients in the placebo group and 8 patients out of 69 in the amisulpride group used antiparkinsonian drugs from the start of the study. During the study antiparkinsonian medication was initiated in one 95

4 Schizophrenia Bulletin, Vol. 28, No. 2, 2002 J.G. Storosum et al. Figure. Mean baseline score, mean improvement on the primary outcome measure, and 95 percent confidence intervals of the difference between amisulpride and placebo SANS SAPS Source Paillere et al. (995) Boyer et al. (995) Loo et al. (997) Treatments Ami. 50 mg Ami. 00 mg Ami. 300 mg Ami. 00 mg Baseline/change SANS 74.9/ / / / A / /-6.7 at endpoint SAPS 5.3/ / / A M / /-0. MADRS 3.2/-5.6.5/ Danion et al. (999) Overall Ami. 50 mg Ami. 00 mg 76J/ A / / / / / / / Note.Ami. = amisulpride; MADRS = Montgomery Asberg Depression Rating Scale; SANS = Scale for the Assessment of Negative Symptoms; SAPS = Scale for the Assessment of Positive Symptoms. The graphs represent the mean differences and 95 percent confidence intervals between amisulpride and placebo on the SANS and SAPS respectively. The overall estimate and confidence intervals were based on a fixed model, weighed for variance differences between the studies. There was no indication for heterogeneity between the studies: x 2 SANS = 4-07 > df=5,p = 0.54; test for heterogeneity: x 2 SAPS = 6-33 > df=5,p = patient in the placebo group and in four patients in the amisulpride group. At the end of the study EPS was still rated as mild in both groups with no statistically significant difference between treatments. In the study of Danion et al. (999), EPS was measured on the Simpson-Angus Rating Scale and the Abnormal Involuntary Movement Scale. EPS was rated as mild in all three treatment groups, which was still the case at endpoint. Two patients received antiparkinsonian drugs in the placebo group and two in the amisulpride 50 mg group. In the studies of Paillere-Martinot et al. (995) and Danion et al. (999), severity of depression was measured. At endpoint a significant difference in mean improvement on the MADRS in favor of the active treatments compared to placebo was observed. Discussion Efficacy on negative symptoms has been associated with classic antipsychotic treatment (Goldberg 985; Meltzer et al. 986) and claimed for clozapine (Kane et al. 988), but this has never been shown in placebo-controlled studies conducted in patients with predominantly negative symptoms. In most of the pivotal short-term randomized placebo-controlled trials of recently developed antischizophrenic agents (Borison et al. 992, 996; Chouinard et al. 993; Marder and Meibach 994; Peuskens et al. 995; Beasley et al. 996a, 996fc; Arvantis et al. 997; Small et al. 997; Tollefson et al. 997; Zimbroff et al. 997; Keck et al. 998; King et al. 998), efficacy on negative symptoms has been claimed. However, because patients with predominantly positive symptoms were included in these studies, these findings might be explained by a primary beneficial effect on positive symptoms, causing secondarily an improvement on the negative symptom score (Moller 993; Moller et al. 994). An improvement on the negative symptom score might also be explained by the lower EPS properties of these new compounds compared to the classic antipsychotics. In conclusion, in these studies it is impossible to disentangle which part of the improvement on negative symptoms is due to the improvement on positive symptoms and which part to less EPS, or to an improvement on depressive symptoms, or to 96

5 lisul B. i p Table 3. Mean (SO) scores on the SANS subscales Source Paillere- Martinot etal. (995) Boyer etal. (995) Loo et al. (997) Treatments Amisulpride 50 mg Amisulpride 00 mg Amisulpride 300 mg Amisulpride 00 mg Affective Baseline 7.2(7.6) 7.7(4.4) (4.8) 20.8 (5.6) Flattening Endpoint 3.0(6.3) 7.9 (5. ) (7.8) 6.0 (8. ) 3 Alogia Baseline Endpoint 9.3 (4.8) 8.9 (3.3) (3.) 0.9(3.) 6.6 (3.3) 8.4 (3.4) (4.5) 8.8 (4.2) 3 Avolition, Apathy Baseline Endpoint 9.9(.4) 9. (2.8) (2.3) 0.6(2.4) 6.7 (3.2) 9.3 (2.7) (3.8) 8.6 (3.8) 3 Anhedonia Baseline 7.7(3.3) 8.5(2.) (2.7) 6. (2.7), Asociality Endpoint 3.2(5.2) 4.9(2.3) (5.2) 3.4 (5.0) 3 Attention Baseline 3.0(.0) 2.2 (0.8) (2.2) 5.3 (2.3) Impairment Endpoint 0.3 (0.2) 2.6 (.2) (3.0) 4.0 (3.0) 3 Note.SANS = Scale for the Assessment of Negative Symptoms; SD = standard deviation. In the publication of Boyer et al. (995) standard deviation data were not provided. In the publication of Danion et al. (999) SANS subscales results were not provided. Amisulpride statistically significant superior to placebo (Mann-Whitney U test, one-tailed). 2 Amisulpride statistically significant superior to placebo (multiple analysis of variance). 3 Amisulpride statistically significant superior to placebo (one-way analysis of variance).

6 Schizophrenia Bulletin, Vol. 28, No. 2, 2002 J.G. Storosum et al. an actual effect on primary negative symptoms. For this reason specific study designs have been developed with the primary objective to show efficacy on primary negative symptoms (Moller et al. 994; Committee on Proprietary Medicinal Products 998). In these studies patients with predominantly negative symptoms ought to be included. Moreover, the patients ought to have low levels of positive symptoms, depressive symptoms, and EPS at baseline, and these symptoms should stay relatively stable during the study. A washout period with sufficiently long duration before the start of the study should ensure that the patients included are free of (depot) medication effects, including EPS. Oral antipsychotic medications have antidopaminergic effects for at least 2 weeks, while depot medications may have these actions for months (Farde et al. 992). Thus, a short period of discontinuation of prior medication (e.g., less than 7 days) is not a "true" medication-free assessment (Harvey and Keefe 200). EPS at baseline can lead to an improvement on the SANS during the study that is a pseudo-improvement of negative symptoms because it might be due only to washout of previously taken classic antispsychotics with the associated EPS. The amisulpride studies conducted to demonstrate efficacy in negative symptoms included patients with predominantly negative symptoms, with low SAPS scores and low scores on EPS scales at baseline. However, depression scores were not rated in two studies (figure ), and in two studies no washout period was observed (table ). In the study of Loo et al. (997), the lack of washout period was not a major shortcoming, as this study had a long duration. The influence of EPS at baseline in both placebo and amisulpride groups has probably been washed out during the study, making fairly implausible the contention that efficacy results at the end are influenced by EPS at baseline. In all studies a significant difference on the SANS was shown in favor of low doses of amisulpride ( mg) compared to placebo. These results are not suggestive for a dose-effect relationship in the dose range between 50 and 300 mg. The improvement on the SANS was not accompanied by a simultaneous improvement on the SAPS or a decrease in EPS in three of the four studies, suggesting efficacy on primary negative symptoms. However, the overall analysis showed a significant improvement on the SAPS in favor of the amisulpride group. Moreover, in the studies where depressive symptoms were measured, a significant improvement was shown in favor of amisulpride also. This might suggest that the effect shown on negative symptoms was due to the improvement on positive symptoms or depressive symptoms. However, the SAPS and MADRS baseline scores were rather low. Therefore the improvement on both scales in favor of amisulpride only has modest clinical impact and is probably not responsible for the improvement on the SANS. Another option for the depression score improvement might be that it is due to the improvement on the SANS. With regard to the SANS it should be noted that this instrument is reliable and valid for rating negative symptoms. However, it was not developed for distinguishing between primary negative symptoms and secondary negative symptoms. Therefore, although the patients included in the studies had high SANS scores at baseline, this was not completely a guarantee that they were the representative population. Maybe not only the use of the SANS but also the use of the Schedule for the Deficit Syndrome (SDS; Kirkpatrick et al. 989, 2000) could be an option in future studies, as this instrument is able to make a distinction between patients with and patients without primary negative symptoms by longitudinal assessment of relevant parameters. This instrument was already used in several studies to distinguish primary from secondary negative symptoms (Conley et al. 994; Buchanan et al. 998; Goff et al. 999; Rosenheck et al. 999; Kopelowicz et al. 2000). An impressive finding in the studies reviewed was the success rate in the placebo groups. It has always been assumed that primary negative symptoms were persistent and stable (Carpenter et al. 988) and improvement was expected to be slower than in positive symptoms."all studies showed, however, a substantial success rate in the placebo group: between 8 percent and 25 percent after 6 weeks, 8 percent after 2 weeks, and 20 percent after 26 weeks. The positive correlation between mean SANS baseline scores and endpoint scores as well as the success rate in the placebo groups might be explained as an example of regression to the mean. Another explanation of these phenomena might be that the concept of primary negative symptoms should be reconsidered and changed according to the theory of Greden and Tandon (99), which was recently summarized by Kopelowicz et al. (2000). In this theory, two types of primary negative symptoms are distinguished: () deficit or primary enduring negative symptoms that are intrinsic to the disease process, and (2) primary nonenduring negative symptoms that are intrinsic to the disorder but wax and wane like positive symptoms. The results of the amisulpride studies indicate that low doses of amisulpride are efficacious on the nonenduring primary negative symptoms and probably not on the enduring primary negative symptoms. As the pharmacodynamic profile of low doses of amisulpride is not indicative to prevent an acute exacerbation, treatment under low doses of amisulpride might increase the risk of relapse or recurrence. What is to be done when a patient who is treated with low doses of amisulpride experiences an exacerbation? 98

7 Amisulpride Schizophrenia Bulletin, Vol. 28, No. 2, 2002 Five active controlled studies in schizophrenia patients with predominately positive symptoms were conducted (Delcker et al. 990; Moller et al. 997; Puech et al. 998; Wetzel et al. 998; Peuskens et al. 999). Amisulpride was given in doses 5 to 0 times higher than in studies in patients with predominantly negative symptoms. However, in studies of schizophrenia there is always the problem of assay sensitivity (the ability of a study to distinguish between active and inactive treatments, Temple and Ellenberg 2000). Because no placebo control was used in these amisulpride studies, efficacy for the traditional treatment of schizophrenia was not demonstrated unequivocally (Storosum et al. 998). Hence, in case of an acute exacerbation under low-dose amisulpride, it is questionable whether increasing the dose is the right strategy. Moreover, it is not clear what will happen with the improvement on negative symptoms because of amisulpride when patients are treated for an acute exacerbation (with positive symptoms). References Andreasen, N. Scale for the Assessment of Negative Symptoms. Iowa City, IA: University of Iowa, 984a. Andreasen, N. Scale for the Assessment of Positive Symptoms. Iowa City, IA: University of Iowa, 984b. American Psychiatric Association. DSMIII: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: APA, 980. American Psychiatric Association. DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed., revised. Washington, DC: APA, 987. American Psychiatric Association. DSM-IV: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: APA, 994. Arvanitis, LA.; Miller, B.G.; and the Seroquel Trial 3 Study Group. Multiple fixed doses of "Seroquel" (quetiapine) in patients with acute exacerbation of schizophrenia: A comparison with haloperidol and placebo. Biological Psychiatry, 42: , 997. Beasley, CM., Jr.; Sanger, T.; Satterlee, W.; Tollefson, G.; Tran, P.; Hamilton, S.; and Olanzapine HGAP Study Group. Olanzapine versus placebo: Results of a doubleblind, fixed dose olanzapine trial. Psychopharmacology, 24:59-67, 996a. Beasley, CM., Jr.; Tollefson, G.; Tran, P.; Satterlee, W.; Sanger, T.; Hamilton, S.; and Olanzapine HGAD Study Group. Olanzapine versus placebo and haloperidol: Acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology, 4:-23, 996b. Borison, R.L.; Arvanitis, L.A.; Miller, B.G.; and the USA Seroquel Study Group. ICI 204,636, an atypical antipsychotic: Efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. Journal of Clinical Psychopharmacology, 6:58-69, 996. Borison, R.L.; Pathiraja, A.P.; Diamand, B.I.; and Meibach, R.C Risperidone: Clinical safety and efficacy in schizophrenia. Psychopharmacology Bulletin, 28:23-28, 992. Boyer, P.; Lecrubier, Y.; Puech, J.; Dewailly, J.; and Aubin, F. Treatment of negative symptoms in schizophrenia with amisulpride. British Journal of Psychiatry, 66:68-72, 995. Buchanan, R.W.; Breier, A.; Kirkpatrick, B.; Ball, P.; and Carpenter, W.T., Jr. Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome. American Journal of Psychiatry, 55:75-760, 998. Carpenter, W.T., Jr.; Heinrichs, D.W.; and Alphs, L.D. Treatment of negative symptoms. Schizophrenia Bulletin, ll(3): , 985. Carpenter, W.T., Jr.; Heinrichs, D.W.; and Wagman, A.M.I. Deficit and nondeficit forms of schizophrenia: The concept. American Journal of Psychiatry, 45: , 988. Chouinard, G.; Jones, B.; Remington, G.; Bloom, D.; Addington, D.; MacEwan, G.W.; Labelle, A.; and Beauclar, L.A. Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. Journal of Clinical Psychopharmacology, 3:25-40, 993. Committee on Proprietary Medicinal Products. Note for Guidance on the Clinical Investigation of Medicinal Products in the Treatment of Schizophrenia. CPMP/EWP/559/95. humans/ewp.htm, 998. Conley, R.; Gounaris, C; and Tamminga, C. Clozapine response varies in deficit versus non-deficit schizophrenic subjects. Biology Psychiatry, 35: , 994. Crow, T.J. The two-syndrome concept: Origins and current status. Schizophrenia Bulletin, (3):47^86, 985. Danion, J-M.; Rein, W.; Fleurot, O.F.; and the Amisulpride Study Group. Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. American Journal of Psychiatry, 56:60-66, 999. Delcker, A.; Schoon, M.L.; Oczkowski, B.; and Gaertner, H.J. Amisulpride versus haloperidol in treatment of schizophrenic patientsresults of a double-blind study. Pharmacopsychiatry, 23:25-30,

8 Schizophrenia Bulletin, Vol. 28, No. 2, 2002 J.G. Storosum et al. Farde, L.; Nordstrom, A-L.; Wiesel, F-A.; Pauli, S.; Halldin, C; and Sedvall, G. Positron emission tomographic analysis of central Dl and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Archives of General Psychiatry, 49: , 992. Feighner, J.P.; Robins, E.; Guze, S.B.; Woodruff, R.A., Jr.; Winokur, G.; and Munoz, R. Diagnostic criteria for use in psychiatric research. Archives of General Psychiatry, 26:57-63, 972. Goff, D.C.; Tsai, G.; Levitt, J.; Amico, E.; Manoach, D.; Schoenfeld, D.A.; Hayden, D.L.; McCarley, R.; and Coyle, J.T. A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. Archives of General Psychiatry, 56:2-27, 999. Goldberg, S.C. Negative and deficit symptoms in schizophrenia do respond to neuroleptics. Schizophrenia Bulletin, ll(3): , 985. Greden, J.F., and Tandon, R., eds. Negative Schizophrenic Symptoms: Pathophysiology and Clinical Implications. Washington, DC: American Psychiatric Press, 99. Harvey, P.D., and Keefe, R.S.E. Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. American Journal of Psychiatry, 58:76-84,200. Kane, J.; Honigfeld, G.; Singer, J.; and Melzer, H. Clozapine for the treatment-resistant schizophrenics: A double-blind comparison with chlorpromazine. Archives of General Psychiatry, 45: , 988. Kay, S.R., and Opler, L.A. The positive-negative dimension in schizophrenia: Its validity and significance. Psychiatric Developments, 2:79-03, 987. Keck, P., Jr.; Buffenstein, A.; Ferguson, J.; Feighner, J.; Jaffe, W.; Harrigan, E.P.; and Morrissey, M.R. Ziprasidone 40 and 20 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: A 4-week placebo-controlled trial. Psychopharmacology, 40:73-84, 998. King, D.J.; Link, C.G.G.; and Kowalcyk, B.A. Comparison of bid and tid dose regimens of quetiapine (Seroquel) in the treatment of schizophrenia. Psychopharmacology, 37:39-46, 998. Kirkpatrick, B.; Buchanan, R.W.; McKennedy, P.D.; Alphs, L.D.; and Carpenter, W.T., Jr. The Schedule for the Deficit Syndrome: An instrument for research in schizophrenia. Psychiatry Research, 30:9-23, 989. Kirkpatrick, B.; Kopelowicz, A.; Buchanan, R.W.; and Carpenter, W.T., Jr. Assessing the efficacy of treatment for the deficit syndrome of schizophrenia. Neuropsychopharmacology, 22:303-30, Kopelowicz, A.; Zarate, R.; Tripodis, K.; Gonzales, V.; and Mintz, J. Differential efficacy of olanzapine for deficit and nondeficit negative symptoms in schizophrenia. American Journal of Psychiatry, 57: , Kraepelin, E. Dementia Praecox and Paraphrenia. (99) Translated by R.M. Barclay. Huntington, NY: Robert E. Krieger, 97. Loo, H.; Poirier-Littre, M-F.; Theron, M.; Rein, W.; and Fleurot, O. Amisulpride versus placebo in the mediumterm treatment of negative symptoms of schizophrenia. British Journal of Psychiatry, 70:8-22, 997. Marder, S.R., and Meibach, R.C. Risperidone in the treatment of schizophrenia. American Journal of Psychiatry, 5: , 994. Meltzer, H.Y.; Sommers, A.A.; and Luchins, D.J. The effect of neuroleptics and other psychotropic drugs on negative symptoms in schizophrenia. Journal of Clinical Psychopharmacology 6: , 986. Moller, H-J. Neuroleptic treatment of negative symptoms in schizophrenic patients: Efficacy problems and methodological difficulties. European Neuropsychopharmacology, 3:-, 993. Moller, H-J.; Boyer, P.; Fleurot, O.; Rein, W; and PROD- ASLP Study Group. Improvement of acute exacerbation of schizophrenia with amisulpride: A comparison with haloperidol. Psychopharmacology, 32:396-40, 997. Moller, H-J.; van Praag, H.M.; Aufdembrinke, B.; Baily, B.; Barnes, T.R.; Beck, J.; Bentsen, H.; Eich, F.X.; Farrow, L.; Fleischhacker, W.W.; Gelach, J.; Grafford, K.; Hentschel, B.; Hertkorn, A.; Heylen, S.; Lecrubier, Y.; Leonard, J.P.; McKenna, P.; Maier, W.; Pederson, V.; Rappard, A.; Rein, W.; Ryan, J.; Sloth Nielsen, M.; Stieglitz, R-D.; Wegener, G.; and Wilson, J. Negative symptoms in schizophrenia: Considerations for clinical trials. Working Group on Negative Symptoms in Schizophrenia. Psychopharmacology, 5:22-228, 994. Paillere-Martinot, M-L.; Lecrubier, Y; Martinot, J-L.; and Aubin, FA. Improvement of some schizophrenic deficit symptoms with low doses of amisulpride. American Journal of Psychiatry, 52:30-33, 995. Perrault, G.; Depoortere, R.; Morel, E.; Sanger, D.J.; and Scatton, B. Psychopharmacological profile of amisulpride: An antipsychotic drug with presynaptic D 2 /D 3, dopamine receptor antagonist activity and limbic selectivity. Journal of Pharmacology and Experimental Therapeutics, 280:73-82, 997. Peuskens, J., and the Risperidone Study Group. Risperidone in the treatment of patients with chronic 200

9 Amisulpride Schizophrenia Bulletin, Vol. 28, No. 2, 2002 schizophrenia: A multinational, multi-center, doubleblind, parallel-group study versus haloperidol. British Journal of Psychiatry, 66:72-726, 995. Peuskens, J.; Bech, P.; Moller, H-J.; Bale, H.J.; Fleurot, O.; and Rein, W. Amisulpride vs. risperidone in the treatment of acute exacerbation of schizophrenia. Amisulpride Study Group. Psychiatry Research, 88:07-7, 999. Puech, A.J.; Fleurot, O.; Rein, W.; and the Amisulpride Study Group. Amisulpride, an atypical antipsychotic, in the treatment of acute episodes of schizophrenia: A doseranging study vs. haloperidol. Acta Psychiatrica Scandinavica, 98:65-72, 998. Rosenheck, R.; Dunn, L.; Peszke, M.; Cramer, J.; Xu, W.; Thomas, J.; and Charney, D. Impact of clozapine on negative symptoms and on the deficit syndrome in refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. American Journal of Psychiatry, 56:88-93, 999. Scatton, B.; Claustre, Y.; Cudennec, A.; Oblin, A.; Perrault, G.; Snager, D.J.; and Schoemaker, H. Amisulpride: From animal pharmacology to therapeutic action. International Clinical Psychopharmacology, 2(Suppl 2):S29-S36, 997. Schneider, K. Clinical Psychopathology. (950) Translated by M.W. Hamilton. New York, NY: Grune and Stratton, 959. Schoemaker, H.; Claustre, Y.; Fage, D.; Rouquir, L.; Chergui, K.; Curet, O.; Oblin, A.; Gonon, F; Carter, C; Benavides, J.; and Scatton, B. Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. Journal of Pharmacology and Experimental Therapeutics, 280:83-97, 997. Small, J.G.; Hirsch, S.R.; Aravantis, L.A.; Miller, B.G.; Link, C.G.G.; and the Seroquel Study Group. Quetiapine in patients with schizophrenia. Archives of General Psychiatry, 54: , 997. Spitzer, R.L.; Endicott, J.E.; and Robins, E. Research Diagnostic Criteria (RDC) for a Selected Group of Functional Disorders. 3rd ed. New York, NY: New York State Psychiatric Institute, Biometric Research Group of Functional Disorders, 977. Storosum, J.G.; Elferink, A.J.A.; and van Zwieten, B.J. Schizophrenia: Do we really need placebo-controlled studies? European Neuropsychopharmacology, 8: , 998. Strauss, J.S.; Carpenter, W.T.; and Bartko, J.J. The diagnosis and understanding of schizophrenia: III. Speculations on the processes that underlie schizophrenic symptoms and signs. Schizophrenia Bulletin, :6-69, 974. Temple, R., and Ellenberg, S.S. -controlled trials and active-control trials in the evaluation of new treatments: I. Ethical and scientific issues. Annals of Internal Medicine, 33: ,2000. Tollefson, G.D.; Beasley, CM., Jr.; Tran, P.V.; Street, J.S.; Krueger, J.A.; Tamura, R.N.; Graffeo, K.A.; and Thiem, M.E. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: Results of an international collaborative trial. American Journal of Psychiatry, 54:457^65, 997. Wetzel, H.; Griinder, G.; Hillert, A.; Philipp, M.; Gattaz, W.F.; Sauer, H.; Adler, G.; Schroder, J.; Rein, W.; Benkert, O.; and the Amisulpride Study Group. Amisulpride versus flupentixol in schizophrenia with predominant positive symptomatologya double-blind controlled study comparing a selective D2-like antagonist to a mixed Dl-/D2-like antagonist. Psychopharmacology, 37: ,998. Zimbroff, D.L.; Kane, J.M.; Tamminga, C.A.; Daniel, D.G.; Mack, R.J.; Wozniak, P.J.; Sebree, T.B.; Wallin, B.A.; Kashkin, M.D.; and the Sertindole Study Group. Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. American Journal of Psychiatry, 54:782-79, 997. The Authors Jitschak G. Storosum, M.D., is Psychiatrist, Medicines Evaluation Board of the Netherlands, Den Haag, the Netherlands, and Psychiatric Department of the Academic Medical Center, Amsterdam, the Netherlands. Andre J.A. Elferink, M.D., Ph.D., is Clinical Epidemiologist; Barbara J. van Zwieten, Ph.D., is Pharmacologist; and Roel van Strik, F.S.S., is Professor of Biostatistics, Medicines Evaluation Board of the Netherlands. Witte J.G. Hoogendijk, M.D., Ph.D., is Psychiatrist, Psychiatric Department of the Free University, Amsterdam. Andre W. Broekmans is Professor of Pharmaceutical Technology Assessment, Medicines Evaluation Board of the Netherlands and Department of Pharmacoepidemiology and Pharmacotherapy, University of Utrecht, Utrecht, the Netherlands. 20

10 Minority Research Training in Psychiatry Through a five-year, $2.5 million grant from the National Institute of Mental Health, the American Psychiatric Institute for Research and Education (APIRE) is seeking through the Program for Minority Research Training in Psychiatry (PMRTP) to increase the number of minority psychiatrists entering the field of psychiatric research. The program provides medical students with funding for stipends, travel expenses, and tuition for an elective or summer experience in a research environment, with special attention paid to trainees' career development in research. In addition, stipends are available for a limited number of one-or two-year postresidency fellowships for minority psychiatrists. Residents may engage in fullyear research training during the last year of psychiatric residency or in "year off' research training. Training takes place at research-oriented departments of psychiatry in major U.S. medical schools and other appropriate sites throughout the country. An individual at the site (the research "mentor") is responsible for overseeing the research training experience. Administered by the American Psychiatric Institute for Research and Education, The program includes outreach efforts to identify minority medical students and residents who are potential researchers and to put them in touch with advisors who counsel them about careers in psychiatric research. Additional activities assist fellows and alumni in their research career development. The director of the PMRTP is James Thompson, M.D., M.P.H.; the project manager is Ernesto Guerra. An advisory committee of senior researchers and minority psychiatrists developed guidelines for applicants and criteria for selection. The members of this committee evaluate and select trainees, oversee the research training experiences, and play a role in evaluating the effectiveness of the program. December is the deadline for applications for residents seeking a year or more of training and for postresidency fellows. For medical students, applications are due three months before training is to begin. Summer medical students who will start their training by June 30 should submit their applications by April. For more information about the PMRTP, call the toll-free number for the PMRTP, , or , eguerra@psych.org, or write to PMRTP at the American Psychiatric Institute for Research and Education, 400 K Street, NW, Washington, DC