- Email: [email protected]
Antipsychotic drug dosing
596
Abmncls
B10L. PSYCHIATRY 19')6;39:500-666
delicils crc:llcd a vulnerability to S·HT.stimulated psychosis, thi!' slUdy evaluated the interdctive effects of the benlodiazepine partial inverse 3gonist, iomllzenil. nnd the S·HT2 pani:lI agonist, MCPP, in healthy subjects. Subjects compl~lcd four t~t days during which they received iomazenil (3.7 JLglkg. tv.) or placebo prior to MCPP to. I mglkg, i.v.) or placebo in a double-blind fashion nnd mndomized order. To date. 5 heallhy subjects compleled testing. Preliminlll'}' data indicale that nchhllr agent evok~-d psychosis when adminislered nlone, but there was a trend for lhe combination of MCPP and iomazenil to increase the four key positive symploms of schizophrenia on the Brief Psychiatric Rating Scale. These crrecl.~ were associated with modl!st degrees of lhought disorder OInd parnnoia. There was also a trend for Ihese agents to produce synergistic increases in anxielY. These preliminary data suggcl>t that iomazenil may potentiate the p!iychotogcnic and anxiogcnic responses of MCPP. If so. then GABAergic uelicits may crcOIte a vulnerability to psychotic states mediated by 5·HT systems.
327. CSF NEUROPEPTIDE DYSREGULATION IN PATIENTS WITH AFFECTIVE DISORDER M.A. Frye l , A.A. Mathe2 , K.A. Gary3, M.S. George4 , G. Cora-Locatelli', T. Hugrins', PJ. Puzzaglia5, A.M. Callnhan6, C. Davis, 1. Marange1l 7, D. Rubinow 1, A. Winokur\ & R.M. Post l I Biological Psychiatry Branch. NIMH, Belhesda, MD: ~Karolinska Institule, Stockholm. Sweden; 3University of Pennsylvania School of Medicine, Philadelphia, Ph; 4Medical University of South C
TX
Multiple neuropcptides havc been impJic
328. PROBLEMS IN POST-MORTEM DIAGNOSIS CAN BE SOLVED L.B. Bigelow 1, E.F. Torrey2, & lE. Kleinman I IClinical Bmin Disordcrs Branch. NIMH Neurosciencl.l Center. Washington, DC 20032, ZStanley Research Found:ltion. NIMH Neuroscience Center, Washington. DC 20032 The Stanley Foundation has funded several sites in Ihe United Slales to hap/cst post·mortem brain samples for USc in research into the etiology lind pathology of schizophrenia and bipolar disorder. In order for Ihis effort to bear fruit it is necessary to establish if at all possible the subject's lifetime diagnosis or diagnoses. To uate 22 of 50 available files have been reviewed by two of us. nu~re was agreement in diagnosis for 17 (77%). Agreed upon diagnoses were: 7 with schizophrenia, 8 with bipolar or major depressive disorder and 2 with otber diagnosis. The disagreement in the remaining 5 generally related to a specific diagnosis versus psychosis not otherwise specified. It is the purpose of this presentation to outline the problems encountered in cstabllshlng an accurate diagnosis lind to present methods for overcoming these difficulties. A frequent problem encountered is clinicians tendency to record only their conclusions (e.g. "the pnlient is delusional") without recording exactly whal was said that Icad to such a statement. Anomer all too common Iindir,g is that after an initial diagnosis is recorded subsequent clinicians will simply repeal the same one even though the facts presented do not support their conclusion. In several instances we required information from living relatives or friends to make up for the record deficiencies. Despite these problems, we have found that by being persistent in requesting records and by interviewing family and signifi. cntH others in the person's life we have been able to establish with a high degree of reliability the diagnosis. A scheme for achieving this goal will ~ presented nlong whh data from the cases reviewcd.
329. ANTIPSYCHOTIC DRUG DOSING J.M. Davis, P. Janicak, & R. Sharma The Psychialric Institute. Department of Psychiatry, University of
Illinois al Chicago. Chicago, IL Most schizophrenics show some degree of pnnial recovery wilh antip~ychOlics. Achieving lhe minimum crfective do~c will avoid to:
Abslracts
mOL PSYCHJATRY 1996:39:500-666
arrive al conclusions as to (A) the threshold dose, llnd (B) whether or not an upper end of It therapeutic window exists where high doses can be counterproductive. Our paper will emphasitc the two part re-randomized design.
330. DOES SEROTONIN BLOCKADE ALTER ANTIPSYCHOTIC DRUG RESPONSE?
597
in medication-free schizophrenic volunteers (n=6) using oral single doses in a btinded design. UH232 across the doseli tested did not improve psychotic symptoms. In fact. some subjecls experienced a tmnsieRt worsening of symptoms. Whereas the strategy of using partial DA agonists for the treatment of schizophrenia appears promising provided the drug action can be eltlcnded, selective DJ dopamine receplor antagonists do not appear to provide antipsychotic aclion.
332. EFFICACY AND SAFETY OF THREE
J.M. Davis, P. Janicak, & R. Sharma
DOSES OF SERTINDOLE AND HALOPERIDOL IN SCHIZOPHRENIC PATIENTS
The Psychiatric Institute, Department of Psychiatry, Univer:;ity of Illinois al Chicaso, Chicago, IL
N. Bark l , R. Mack2, J. Zborowski, D. Morris, T. Sebree, S. Shook, & B. Wallin
We now have data on lhe clinical efficacy of II variety of drugs which block both dopamine~ family of receptors and 5HT':l' as well as those drugs that block dopamine~ receptors without affecting serotonin receptors. While clozupinc has many other phammcotogic
'Bronx Psychiatric Center. Dronx, NY; :%PJ:ychopharmacology Venture, Abboll Laboratories. Abbott Park, IL
331. TREATMENT OF SCHIZOPHRENIA: NEW ANTIDOPAMINERGIC STRATEGIES
A.C. Lahti, M.A. Weiler, P.K. Corey, D.T. Warfel, R.A. Lahti A. Carlsson, & C.A, Tamminga l
Maryland. Psychiatric Research Center. Univer5ity of Maryland School of Medicine, P.D Box 21247, Baltimore, MD 21228 New antidopaminergic pharmacologic strntcgics in lichizophrenia might contribute to improved lhempeulic efficacy and reduced side! effects. Partial dopamine! 02 uqonists (PDA) have preferential affinil)' for the dopamine! (DA) nutoreceplor and reduce DA synthesis and retease (rom DA ncurons. nnd thus potentially could exert n neuroleptic-like effect. (-)-3PPP is u PDA with 35% intrinsic activity (IA) at the 0:: receptor; it was tested for efficocy in drug-free schizophrenic patients. A preliminary study (n=9) suggestcd thaI the dntg had a short-lived antipsychotic action, probably relnted to the development of tolerance. We have subsequently demonstrated thnl (+3PPP exerted a significant antipsychotic effect aner one week of treatrnent in a placebo-controlled trial. Strategies to minimize tolerance and extend drug action are now being teslcd. Selective D,ldoparnine receptor antugonist, UH232 is an amino tetrillin with preferential 4:1 nflinity for the DJ receptor; these receplors nrc loented predominantly in the nucleus accumbcns. UH232 was tested
Scrtindole, discovered nnd patented by H. Lundbeck (Denmark) and licensed in lhe United Stutes by Abbott L:tboratories, iii a new compound wilh a selective ilntllgonistic activity at dopamine D~ and serolonin S-HT:l receptors, as well as ai-adrenergic llntal;onist activity. Scrtindoll: combines a selective nntagonist effect on mesolimbic dopamine neurons as demonslrated in ill I'i~'o animal experiments with a serotoncrgic antago> nist effect. Such a compound might be cXpl."Cled to improve the symptoms of schizophrenia wilh minimal neurological side effccts. Two large phnse IlJ studies completed in 1995 demonstrate the efficacy and sllfclY of scrtindole versus haloperidol and placebo. The PANSS Totlll Score wll." lhl:: primary efficacy variable for both studies, and EPS was measured by three diffet'Cnt parameters: EPS-relatcrladverse evenls, use of antj-EPS medications, and lhree movcment rating scales (SAS. BAS, and AIMS)_ Doth studies were double-blind. placebo-comrolled, fixed dose. mndornized, eight week lrials in inpaticnl schizophrenics. Study M93-098 examined two doses of sertimlolc (20 mg and 24 mg), llnd haloperidol 16mB, while Study M93- 113 cKumincd three doses of scrtindole (12mg, 20mg, :md 24mg), nnd three doses of haloperidol (4mg, 8mg nnd 16mg). Doth studies demonslrated that scrtindoJe in the range of 12 - 24 mg/day is effective in the trealment of the positive and negative symploms of schizophrenia. It was also established lhut sertindotc and placebo arc clinically and stiltistically indistinguishable wlten compared using: the pereent of pUlients udministercd anli·EPS medicntions; the percent of palients reporting EPS-related treatment-emergent adverse evcnls: and in the change from bllseline in Parkin~onian symptoms and akllthisia a~ measured by the Simpson-Angus Scale (SAS) :lOlJ Bomes Aknthisia Scale (BAS), respectively. In adt.lilion hnloperidol (4 mg. 8 mg. and 16 mglrlay) caused statistically signilicantly more EPS compared to both sertindole and placebo using the same measures. Serlindole is effective in the treatment of the manifestations of psychosis, without the extrapymmidlll symptoms seen with equally efficacious doses of haloperitlol.
333. A MULTIPLE FIXED-DOSE. PLACEBO-
CONTROLLED TRIAL WITH 'SEROQUEL': AN ATYPICAL ANTIPSYCHOTIC R.L. Borison l , L.A. Arvanitis2 , & B.G. Miller 'Medical College of Georgia, Augusta. OA 30912; :!Zcneca Phamlllceuticais. Wilmington. DE 19850 'Scroqucl' (lei 204,636). a dibenzOlhillzepinc with Jflinity for multiple brain receptors, is a new Iltypicalllnlipsycbotic agent for the treillment of
Abmncls
B10L. PSYCHIATRY 19')6;39:500-666
delicils crc:llcd a vulnerability to S·HT.stimulated psychosis, thi!' slUdy evaluated the interdctive effects of the benlodiazepine partial inverse 3gonist, iomllzenil. nnd the S·HT2 pani:lI agonist, MCPP, in healthy subjects. Subjects compl~lcd four t~t days during which they received iomazenil (3.7 JLglkg. tv.) or placebo prior to MCPP to. I mglkg, i.v.) or placebo in a double-blind fashion nnd mndomized order. To date. 5 heallhy subjects compleled testing. Preliminlll'}' data indicale that nchhllr agent evok~-d psychosis when adminislered nlone, but there was a trend for lhe combination of MCPP and iomazenil to increase the four key positive symploms of schizophrenia on the Brief Psychiatric Rating Scale. These crrecl.~ were associated with modl!st degrees of lhought disorder OInd parnnoia. There was also a trend for Ihese agents to produce synergistic increases in anxielY. These preliminary data suggcl>t that iomazenil may potentiate the p!iychotogcnic and anxiogcnic responses of MCPP. If so. then GABAergic uelicits may crcOIte a vulnerability to psychotic states mediated by 5·HT systems.
327. CSF NEUROPEPTIDE DYSREGULATION IN PATIENTS WITH AFFECTIVE DISORDER M.A. Frye l , A.A. Mathe2 , K.A. Gary3, M.S. George4 , G. Cora-Locatelli', T. Hugrins', PJ. Puzzaglia5, A.M. Callnhan6, C. Davis, 1. Marange1l 7, D. Rubinow 1, A. Winokur\ & R.M. Post l I Biological Psychiatry Branch. NIMH, Belhesda, MD: ~Karolinska Institule, Stockholm. Sweden; 3University of Pennsylvania School of Medicine, Philadelphia, Ph; 4Medical University of South C
TX
Multiple neuropcptides havc been impJic
328. PROBLEMS IN POST-MORTEM DIAGNOSIS CAN BE SOLVED L.B. Bigelow 1, E.F. Torrey2, & lE. Kleinman I IClinical Bmin Disordcrs Branch. NIMH Neurosciencl.l Center. Washington, DC 20032, ZStanley Research Found:ltion. NIMH Neuroscience Center, Washington. DC 20032 The Stanley Foundation has funded several sites in Ihe United Slales to hap/cst post·mortem brain samples for USc in research into the etiology lind pathology of schizophrenia and bipolar disorder. In order for Ihis effort to bear fruit it is necessary to establish if at all possible the subject's lifetime diagnosis or diagnoses. To uate 22 of 50 available files have been reviewed by two of us. nu~re was agreement in diagnosis for 17 (77%). Agreed upon diagnoses were: 7 with schizophrenia, 8 with bipolar or major depressive disorder and 2 with otber diagnosis. The disagreement in the remaining 5 generally related to a specific diagnosis versus psychosis not otherwise specified. It is the purpose of this presentation to outline the problems encountered in cstabllshlng an accurate diagnosis lind to present methods for overcoming these difficulties. A frequent problem encountered is clinicians tendency to record only their conclusions (e.g. "the pnlient is delusional") without recording exactly whal was said that Icad to such a statement. Anomer all too common Iindir,g is that after an initial diagnosis is recorded subsequent clinicians will simply repeal the same one even though the facts presented do not support their conclusion. In several instances we required information from living relatives or friends to make up for the record deficiencies. Despite these problems, we have found that by being persistent in requesting records and by interviewing family and signifi. cntH others in the person's life we have been able to establish with a high degree of reliability the diagnosis. A scheme for achieving this goal will ~ presented nlong whh data from the cases reviewcd.
329. ANTIPSYCHOTIC DRUG DOSING J.M. Davis, P. Janicak, & R. Sharma The Psychialric Institute. Department of Psychiatry, University of
Illinois al Chicago. Chicago, IL Most schizophrenics show some degree of pnnial recovery wilh antip~ychOlics. Achieving lhe minimum crfective do~c will avoid to:
Abslracts
mOL PSYCHJATRY 1996:39:500-666
arrive al conclusions as to (A) the threshold dose, llnd (B) whether or not an upper end of It therapeutic window exists where high doses can be counterproductive. Our paper will emphasitc the two part re-randomized design.
330. DOES SEROTONIN BLOCKADE ALTER ANTIPSYCHOTIC DRUG RESPONSE?
597
in medication-free schizophrenic volunteers (n=6) using oral single doses in a btinded design. UH232 across the doseli tested did not improve psychotic symptoms. In fact. some subjecls experienced a tmnsieRt worsening of symptoms. Whereas the strategy of using partial DA agonists for the treatment of schizophrenia appears promising provided the drug action can be eltlcnded, selective DJ dopamine receplor antagonists do not appear to provide antipsychotic aclion.
332. EFFICACY AND SAFETY OF THREE
J.M. Davis, P. Janicak, & R. Sharma
DOSES OF SERTINDOLE AND HALOPERIDOL IN SCHIZOPHRENIC PATIENTS
The Psychiatric Institute, Department of Psychiatry, Univer:;ity of Illinois al Chicaso, Chicago, IL
N. Bark l , R. Mack2, J. Zborowski, D. Morris, T. Sebree, S. Shook, & B. Wallin
We now have data on lhe clinical efficacy of II variety of drugs which block both dopamine~ family of receptors and 5HT':l' as well as those drugs that block dopamine~ receptors without affecting serotonin receptors. While clozupinc has many other phammcotogic
'Bronx Psychiatric Center. Dronx, NY; :%PJ:ychopharmacology Venture, Abboll Laboratories. Abbott Park, IL
331. TREATMENT OF SCHIZOPHRENIA: NEW ANTIDOPAMINERGIC STRATEGIES
A.C. Lahti, M.A. Weiler, P.K. Corey, D.T. Warfel, R.A. Lahti A. Carlsson, & C.A, Tamminga l
Maryland. Psychiatric Research Center. Univer5ity of Maryland School of Medicine, P.D Box 21247, Baltimore, MD 21228 New antidopaminergic pharmacologic strntcgics in lichizophrenia might contribute to improved lhempeulic efficacy and reduced side! effects. Partial dopamine! 02 uqonists (PDA) have preferential affinil)' for the dopamine! (DA) nutoreceplor and reduce DA synthesis and retease (rom DA ncurons. nnd thus potentially could exert n neuroleptic-like effect. (-)-3PPP is u PDA with 35% intrinsic activity (IA) at the 0:: receptor; it was tested for efficocy in drug-free schizophrenic patients. A preliminary study (n=9) suggestcd thaI the dntg had a short-lived antipsychotic action, probably relnted to the development of tolerance. We have subsequently demonstrated thnl (+3PPP exerted a significant antipsychotic effect aner one week of treatrnent in a placebo-controlled trial. Strategies to minimize tolerance and extend drug action are now being teslcd. Selective D,ldoparnine receptor antugonist, UH232 is an amino tetrillin with preferential 4:1 nflinity for the DJ receptor; these receplors nrc loented predominantly in the nucleus accumbcns. UH232 was tested
Scrtindole, discovered nnd patented by H. Lundbeck (Denmark) and licensed in lhe United Stutes by Abbott L:tboratories, iii a new compound wilh a selective ilntllgonistic activity at dopamine D~ and serolonin S-HT:l receptors, as well as ai-adrenergic llntal;onist activity. Scrtindoll: combines a selective nntagonist effect on mesolimbic dopamine neurons as demonslrated in ill I'i~'o animal experiments with a serotoncrgic antago> nist effect. Such a compound might be cXpl."Cled to improve the symptoms of schizophrenia wilh minimal neurological side effccts. Two large phnse IlJ studies completed in 1995 demonstrate the efficacy and sllfclY of scrtindole versus haloperidol and placebo. The PANSS Totlll Score wll." lhl:: primary efficacy variable for both studies, and EPS was measured by three diffet'Cnt parameters: EPS-relatcrladverse evenls, use of antj-EPS medications, and lhree movcment rating scales (SAS. BAS, and AIMS)_ Doth studies were double-blind. placebo-comrolled, fixed dose. mndornized, eight week lrials in inpaticnl schizophrenics. Study M93-098 examined two doses of sertimlolc (20 mg and 24 mg), llnd haloperidol 16mB, while Study M93- 113 cKumincd three doses of scrtindole (12mg, 20mg, :md 24mg), nnd three doses of haloperidol (4mg, 8mg nnd 16mg). Doth studies demonslrated that scrtindoJe in the range of 12 - 24 mg/day is effective in the trealment of the positive and negative symploms of schizophrenia. It was also established lhut sertindotc and placebo arc clinically and stiltistically indistinguishable wlten compared using: the pereent of pUlients udministercd anli·EPS medicntions; the percent of palients reporting EPS-related treatment-emergent adverse evcnls: and in the change from bllseline in Parkin~onian symptoms and akllthisia a~ measured by the Simpson-Angus Scale (SAS) :lOlJ Bomes Aknthisia Scale (BAS), respectively. In adt.lilion hnloperidol (4 mg. 8 mg. and 16 mglrlay) caused statistically signilicantly more EPS compared to both sertindole and placebo using the same measures. Serlindole is effective in the treatment of the manifestations of psychosis, without the extrapymmidlll symptoms seen with equally efficacious doses of haloperitlol.
333. A MULTIPLE FIXED-DOSE. PLACEBO-
CONTROLLED TRIAL WITH 'SEROQUEL': AN ATYPICAL ANTIPSYCHOTIC R.L. Borison l , L.A. Arvanitis2 , & B.G. Miller 'Medical College of Georgia, Augusta. OA 30912; :!Zcneca Phamlllceuticais. Wilmington. DE 19850 'Scroqucl' (lei 204,636). a dibenzOlhillzepinc with Jflinity for multiple brain receptors, is a new Iltypicalllnlipsycbotic agent for the treillment of