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Do biological findings help to identify a risk group?
S. 01. Early intervention and relapse prevention in schizophrenia
$82
[9] Cornblatt BA, Lencz T, Kane JM: Treatment of the schizophrenia prodrome: is it presently ethical? Schizophr Res 2001;51(1):31-38
•
Atypical neuroleptics in prevention of relapse in schizophrenia
D. Naber, E Andersohn. University of Hamburg, Department of
Psychiatry, Hamburg, Germany
~ D o
biological findings help to identify a risk group?
R.S. Kahn. Department of Psychiatry, University Medical Center,
Utrecht, The Netherlands Structural brain abnormalities have consistently been found in schizophrenia. These brain abnormalities appear mostly in gray matter and are localized in the temporal lobes, hippocampus, frontal lobes, thalamus, amygdala and cyngulate (Hulshoff Pol et al., 2001). Interestingly, some of these abnormalities have also been found in first degree relatives of schizophrenic patients. For instance, thalamic abnormalities (Staal et al., 1998), but not frontal lobe abnormalities (Staal et al., 2000) have been found in siblings of schizophrenic patients. Moreover, gray matter abnormalities have been found in monozygotic and to a lesser extent dyzygotic twins of schizophrenic patients (Baar6 et al., 2001). These findings suggest that some of the brain abnormalities found in schizophrenic patients may be related to the endophenotype, i.e. may be related to increase risk of schizophrenia. If these abnormalities are indeed present in subjects at risk, one would also expect some of these abnormalities to be found in early episode never medicated patients. Indeed, abnormalities have been found in midline structures of never medicated schizophrenia patients (Cahn et al., in press and Gilbert et al., 2001). In combination, these data suggest that some of the brain abnormalities found in schizophrenic patients can also be found in first degree relatives of these patients and may be similar to those found in never medicated schizophrenia patients. These abnormalities may serve as endophetypes since some of them are highly genetically controlled (Hulshoff Pol et al., 2002. Studies examining genes expressed in these structures such as the thalamus may provide a clue into the pathogenesis of schizophrenia.
References [1] HulshoffPol, H.E.; Schnack, H.G.; Mandl, R.C.W.;van Haren, N.E.M.; Koning, H.; Collins, D.L.; Evans, A.C.; Kahn, R.S. Focal gray matter density changes in schizophrenia. Archives of General Psychiatry, 2001;58:1118-1125. [2] Staal, W.G.; Hulshoff Pol, H.E., Schnack, H.; Van der Schot, A.C.; Kahn R.S. Partial volume decrease of the thalamus in relatives of patients with schizophrenia. American Journal of Psychiatry, 1998, 155:784-1786. [3] Staal, W.G.;HulshoffPol, H.E.; Schnack, H.G.; Hoogendoorn,M.L.C.; Jellema, K.; Kahn, R.S. Structural brain abnormalities in patients with schizophrenia and their healthy siblings. American Journal of Psychiatry, 2000; 157:416-421. [4] Baar~, W.EC.; Van Oel, J.; HulshoffPol, H.E.; Schnack,H.G.; Durston, S.; Sitskoorn, M.M.; Kahn, R.S. Volumes of brain structures in twins discordant for schizophrenia. Archives of General Psychiatry, 2001;58:33-40. [5] Cahn, W.; Hulshoff Pol, H.E., Bongers, M.; Schnack, H.G., Mandl, R.; van Haren, N.; Durston, S.; Koning, H.; van der Linden, J.A.; Kahn, R.S. Brain morphology in antipsychotic-naiveschizophrenia: a study on multiple brain structures. British Journal of Psychiatry supplement, in press. [6] Gilbert, A.R.; Rosenberg, D.R.; Harenski, K.; Spencer, S.; Sweeney, J.A.; Keskavan, M.S. Thalamic volumes in patients with first-episode schizophrenia. American Journal of Psychiatry, 2001; 158:618-624.
Atypical antipsychotic agents have been found to be effective in the treatment of acute and chronic schizophrenia. Compared to typical neuroleptics they are preferred by patients, produce significantly less extrapyramidal side effects and improve negative, cognitive and affective symptoms. Randomised, controlled longterm trials with prevention of relapse or re-hospitalisation for psychiatric reasons as main outcome criterion are scarce. The following review presents data for five atypical antipsychotic agents. Amisulpride has been shown to be effective (at least to the same degree as haloperidol) in short-term and long-term treatment of schizophrenia (improvements in Quality of Life and in Global Assessment of Functioning). Up to now, studies dealing with prevention of relapse are missing. Clozapine is a widely used antipsychotic drug and has been found to improve even therapy refractory schizophrenia. Because of the well known possible side effect (agranulocytosis), it is used as second-line medication in non-responders to other antipsychotic drugs. In one long-term (one year) randomised, double-blind trial against haloperidol, patients assigned to clozapine had fewer mean days of hospitalisation for psychiatric reasons than patients assigned to haloperidol (143.8 vs. 168.1 days). In an open-label study, patients treated with clozapine experienced significantly fewer relapses and hospitalisations during treatment than in the previous year. Olanzapine proved superior in a double-blind, long-term (12 months), randomised trial against placebo, with relapse defined as hospitalisation because of psychopathology. In another doubleblind, randomised trial against haloperidol, patients treated with olanzapine were significantly less likely to require subsequent hospitalisation compared to haloperidol-treated patients. A doubleblind comparison of olanzapine versus risperidone (28 weeks) revealed that a greater proportion of the olanzapine-treated than risperidone-treated patients maintained their response. Quetiapine is a new atypical antipsychotic, which has been found to reduce psychotic symptoms in acute schizophrenia. No controlled trials with quetiapine in maintenance therapy have been published so far. A recently published trial tested the relapse risk in treatment with risperidone. In a double-blind, long-term (12 months), randomised trial against haloperidol, significantly less relapses were reported for risperidone treatment (34% vs. 60%). In an openlabel study the number of days spent in hospitals was significantly reduced during two years of treatment with risperidone. Another open, long-term study (18 months) revealed that 82.1% of the treated patients continued risperidone medication without relapse. In conclusion, most controlled trials with atypical neuroleptics in the treatment of schizophrenia deal with the short-term effects of this medication. This may be due to methodological or organisational problems of medium- and long-term trials. Nevertheless, atypical neuroleptics seem indicated for maintenance therapy because of numerous positive results (e.g. positive effects on quality of life, negative symptoms and refractory schizophrenia; significantly less extrapyramidal symptoms). More controlled, long-term trials are necessary in order to conduct an evidencebased long-term treatment of schizophrenia.
$82
[9] Cornblatt BA, Lencz T, Kane JM: Treatment of the schizophrenia prodrome: is it presently ethical? Schizophr Res 2001;51(1):31-38
•
Atypical neuroleptics in prevention of relapse in schizophrenia
D. Naber, E Andersohn. University of Hamburg, Department of
Psychiatry, Hamburg, Germany
~ D o
biological findings help to identify a risk group?
R.S. Kahn. Department of Psychiatry, University Medical Center,
Utrecht, The Netherlands Structural brain abnormalities have consistently been found in schizophrenia. These brain abnormalities appear mostly in gray matter and are localized in the temporal lobes, hippocampus, frontal lobes, thalamus, amygdala and cyngulate (Hulshoff Pol et al., 2001). Interestingly, some of these abnormalities have also been found in first degree relatives of schizophrenic patients. For instance, thalamic abnormalities (Staal et al., 1998), but not frontal lobe abnormalities (Staal et al., 2000) have been found in siblings of schizophrenic patients. Moreover, gray matter abnormalities have been found in monozygotic and to a lesser extent dyzygotic twins of schizophrenic patients (Baar6 et al., 2001). These findings suggest that some of the brain abnormalities found in schizophrenic patients may be related to the endophenotype, i.e. may be related to increase risk of schizophrenia. If these abnormalities are indeed present in subjects at risk, one would also expect some of these abnormalities to be found in early episode never medicated patients. Indeed, abnormalities have been found in midline structures of never medicated schizophrenia patients (Cahn et al., in press and Gilbert et al., 2001). In combination, these data suggest that some of the brain abnormalities found in schizophrenic patients can also be found in first degree relatives of these patients and may be similar to those found in never medicated schizophrenia patients. These abnormalities may serve as endophetypes since some of them are highly genetically controlled (Hulshoff Pol et al., 2002. Studies examining genes expressed in these structures such as the thalamus may provide a clue into the pathogenesis of schizophrenia.
References [1] HulshoffPol, H.E.; Schnack, H.G.; Mandl, R.C.W.;van Haren, N.E.M.; Koning, H.; Collins, D.L.; Evans, A.C.; Kahn, R.S. Focal gray matter density changes in schizophrenia. Archives of General Psychiatry, 2001;58:1118-1125. [2] Staal, W.G.; Hulshoff Pol, H.E., Schnack, H.; Van der Schot, A.C.; Kahn R.S. Partial volume decrease of the thalamus in relatives of patients with schizophrenia. American Journal of Psychiatry, 1998, 155:784-1786. [3] Staal, W.G.;HulshoffPol, H.E.; Schnack, H.G.; Hoogendoorn,M.L.C.; Jellema, K.; Kahn, R.S. Structural brain abnormalities in patients with schizophrenia and their healthy siblings. American Journal of Psychiatry, 2000; 157:416-421. [4] Baar~, W.EC.; Van Oel, J.; HulshoffPol, H.E.; Schnack,H.G.; Durston, S.; Sitskoorn, M.M.; Kahn, R.S. Volumes of brain structures in twins discordant for schizophrenia. Archives of General Psychiatry, 2001;58:33-40. [5] Cahn, W.; Hulshoff Pol, H.E., Bongers, M.; Schnack, H.G., Mandl, R.; van Haren, N.; Durston, S.; Koning, H.; van der Linden, J.A.; Kahn, R.S. Brain morphology in antipsychotic-naiveschizophrenia: a study on multiple brain structures. British Journal of Psychiatry supplement, in press. [6] Gilbert, A.R.; Rosenberg, D.R.; Harenski, K.; Spencer, S.; Sweeney, J.A.; Keskavan, M.S. Thalamic volumes in patients with first-episode schizophrenia. American Journal of Psychiatry, 2001; 158:618-624.
Atypical antipsychotic agents have been found to be effective in the treatment of acute and chronic schizophrenia. Compared to typical neuroleptics they are preferred by patients, produce significantly less extrapyramidal side effects and improve negative, cognitive and affective symptoms. Randomised, controlled longterm trials with prevention of relapse or re-hospitalisation for psychiatric reasons as main outcome criterion are scarce. The following review presents data for five atypical antipsychotic agents. Amisulpride has been shown to be effective (at least to the same degree as haloperidol) in short-term and long-term treatment of schizophrenia (improvements in Quality of Life and in Global Assessment of Functioning). Up to now, studies dealing with prevention of relapse are missing. Clozapine is a widely used antipsychotic drug and has been found to improve even therapy refractory schizophrenia. Because of the well known possible side effect (agranulocytosis), it is used as second-line medication in non-responders to other antipsychotic drugs. In one long-term (one year) randomised, double-blind trial against haloperidol, patients assigned to clozapine had fewer mean days of hospitalisation for psychiatric reasons than patients assigned to haloperidol (143.8 vs. 168.1 days). In an open-label study, patients treated with clozapine experienced significantly fewer relapses and hospitalisations during treatment than in the previous year. Olanzapine proved superior in a double-blind, long-term (12 months), randomised trial against placebo, with relapse defined as hospitalisation because of psychopathology. In another doubleblind, randomised trial against haloperidol, patients treated with olanzapine were significantly less likely to require subsequent hospitalisation compared to haloperidol-treated patients. A doubleblind comparison of olanzapine versus risperidone (28 weeks) revealed that a greater proportion of the olanzapine-treated than risperidone-treated patients maintained their response. Quetiapine is a new atypical antipsychotic, which has been found to reduce psychotic symptoms in acute schizophrenia. No controlled trials with quetiapine in maintenance therapy have been published so far. A recently published trial tested the relapse risk in treatment with risperidone. In a double-blind, long-term (12 months), randomised trial against haloperidol, significantly less relapses were reported for risperidone treatment (34% vs. 60%). In an openlabel study the number of days spent in hospitals was significantly reduced during two years of treatment with risperidone. Another open, long-term study (18 months) revealed that 82.1% of the treated patients continued risperidone medication without relapse. In conclusion, most controlled trials with atypical neuroleptics in the treatment of schizophrenia deal with the short-term effects of this medication. This may be due to methodological or organisational problems of medium- and long-term trials. Nevertheless, atypical neuroleptics seem indicated for maintenance therapy because of numerous positive results (e.g. positive effects on quality of life, negative symptoms and refractory schizophrenia; significantly less extrapyramidal symptoms). More controlled, long-term trials are necessary in order to conduct an evidencebased long-term treatment of schizophrenia.