Quality management and quality control of health services have become increasingly important. Cen... more Quality management and quality control of health services have become increasingly important. Central to the concept of quality of care is the consumer's (the patient's) own view of the care provided. UKU (Udvalg for Kliniske Underseøelser), a task force within the Scandinavian Society for Psychopharmacology, has designed a brief consumer satisfaction rating scale, the UKU-ConSat. The UKU-ConSat rating scale was applied in a randomised comparative two-year study of two community-based treatment programs. The study included 84 patients with schizophrenic disorders according to DSM-IV. The major finding was a significantly increased consumer satisfaction with the new community-based program “Integrated Care” in comparison with best-established practice, called “Rational Rehabilitation.” Thus, the new UKU-ConSat rating scale can detect differences, not only for in-patients as has previously been shown, but also between programs in community care settings. By per item analysis it was possible to discriminate between various elements of consumer satisfaction. There were significant correlations between the UKU-ConSat total scores and other clinical outcome domains, viz. symptoms, social function, and patient as well as carer's distress. To conclude, the UKU-ConSat rating scale is suitable for quality management and monitoring of treatment programs in mental health services.
Studies in animals have shown that the rates of synthesis and turnover of catecholamines (CAs), r... more Studies in animals have shown that the rates of synthesis and turnover of catecholamines (CAs), rather than their levels, reflect changes in the functional activity of adrenergic nerves both in the central nervous system (CNS) and periphery (Costa and Neff, 1966; Costa, 1970; Sedvall, Weise and Kopin, 1968). Since a role for CAs has been implied in many physiological and pathological processes in man such as stress, hormone release, temperature regulation, affective disorders, schizophrenia and hypertension, there has been an interest in developing methods to study CA turnover in humans. The techniques which have been successfully utilised in animals can be divided into ‘steady state’ and ‘non-steady state’ methods. The former methods have advantages over the latter in as much as the analysis does not necessarily involve a perturbation of the system. The most common ‘steady state’ methods are: (1) labelling of the CA stores with radioactive amine and following decay; (2) measuring rate of formation of labelled amine after injection or infusion of the labelled precursor amino acid. ‘Non-steady state’ methods usually employ inhibitors of catecholamine synthesis, metabolism or metabolite transport and measure rates of accumulation or disappearance of the CA or metabolite.
Recent progress in a project aiming at developing selective 5-HT1A-receptor agonists and antagoni... more Recent progress in a project aiming at developing selective 5-HT1A-receptor agonists and antagonists is reviewed. A large number of analogues of 8-OH-DPAT has been synthesized, and throughout, we have attempted to prepare enantiopure derivatives. Modifications have been concentrated to the N-alkyl substituents, and substitutions in the C1, C2 and C3-positions. The synthetic strategies and procedures are discussed. A number of interesting observations have been made. Affinity, efficacy and stereoselectivity are modified by the various substitutions. The results have been used to deduce a 3D-model for 5-HT1A-receptor agonists. Recently, Pd-catalyzed reactions have been utilized to prepare a number of pharmacologically interesting analogues of 8-OH-DPAT with various C8-substituents. We have also succeeded to convert the agonist 8-OH-DPAT into an antagonist by introduction of a C5-fluoro substituent, producing (S)-UH-301. The pharmacology of this selective 5-HT1A-receptor antagonist is discussed.
Griffith, 0. R., Marshall, J., Nasmyth, P. A. (1978) Moncada, S., Bunting, S . , Mullane, K., Tho... more Griffith, 0. R., Marshall, J., Nasmyth, P. A. (1978) Moncada, S., Bunting, S . , Mullane, K., Thorogood, Ibid. 64: 416P P., Vane, J. R., Raz, A,, IYeedleman, P. (1977) Hoffman, B. B., DeLean, A,, Wood, C. L., Schocken, D. D., Lefkowitz, R. J. (1979) Life Sci. 24: 1739-1746 Pearce, P. H., Wright, J. M., Egan, C. M., Scrutton, Hsu, C. Y . , Knapp, D. A,, Halushka, P. V. (1979) J. Pharmacol. Exp. Ther. 208: 366-375 Prostaglandins 13: 611-618
The centrally active muscarinic agonist, oxotremorine, elicited an up to 2-fold dose-dependent (0... more The centrally active muscarinic agonist, oxotremorine, elicited an up to 2-fold dose-dependent (0.25-1.5 mg/kg) increase in the activity of tyrosine hydroxylase (TH) in the rat nucleus locus coeruleus (LC) and adrenal medulla. The response occurred in LC after 24 to 48 hours and in adrenal medulla by 4 to 8 hours, peaked in LC at 72 hours and adrenal medulla at 16 to 24 hours and persisted up to 2 weeks in both tissues. In brain the effect appeared confined to cell bodies of noradrenergic neurons. The activity of dopamine beta-hydroxylase increased in adrenal medulla (40%) but not in brain. Immunotitration with anti-TH serum demonstrated that the increase of TH activity in LC is due to increased catalytic activity (activation), whereas in adrenal medulla it is due to a transynaptically mediated accumulation of enzyme protein (induction). Physostigmine (1.0 mg/kg), pilocarpine (25-50 mg/kg) and nicotine (10 mg/kg) increased TH activity in LC and adrenal. We conclude that stimulation of central cholinergic receptors of the muscarinic type results in a delayed and protracted activaiton of TH but not of dopamine beta-hydroxylase in cell bodies of central noradrenergic neurons, and reflexly, to transynaptic induction of TH and dopamine beta-hydroxylase in the adrenal medulla.
The selective 5-hydroxytryptamine (5-HT1A) receptor agonist 8-hydroxy-2-(dipropylamino)tetralin (... more The selective 5-hydroxytryptamine (5-HT1A) receptor agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) induces a large number of pharmacological effects. In the present study we demonstrate that a novel 8-OH-DPAT analog, (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-UH-301], is able to antagonize completely the following (R)-8-OH-DPAT-induced effects in the rat: 1) reduction in brain 5-HT biosynthesis, measured as a decreased 5-hydroxytryptophan-accumulation after decarboxylase inhibition; 2) induction of the 5-HT1A behavior (flat body posture, forepaw treading and hindlimb abduction) in reserpine-pretreated animals; 3) reduction of body temperature; 4) inhibition of the cage-leaving response; and 5) reduction of 5-hydroxytryptophan- and quipazine-induced wet dog shakes. In addition, (S)-UH-301 reverses the 5-HT-induced inhibition of the forskolin stimulated cyclic AMP production in rat hippocampus without producing any effects per se in this assay. It is shown that high doses of (S)-UH-301 decrease rat brain biosynthesis of dopamine. These and previous data indicate that (S)-UH-301 also is a weakly potent dopamine-receptor agonist, but with a lower affinity for D2 as compared to 5-HT1A receptors. Thus, the data suggest that (S)-UH-301 is a 5-HT1A-receptor antagonist without intrinsic activity. Therefore, it is likely that (S)-UH-301 will become a valuable pharmacological tool in future 5-HT research.
Objective: The aim of the study was to assess whether the auditory brainstem response (ABR) profi... more Objective: The aim of the study was to assess whether the auditory brainstem response (ABR) profiling test for schizophrenia would recognize schizoaffective disorder patients as schizophrenia or not. Method: Male and female schizoaffective disorder patients (n=16) from the psychosis unit at Uppsala University Hospital were investigated. Coded sets of randomized ABR recordings intermingled with patients with schizophrenia, adult attention-deficit hyperactivity disorder (ADHD) and healthy controls, were analyzed by an independent party blinded to clinical diagnoses. Results: The ABR profiling test for schizophrenia was positive in 5/16 patients (31%) and negative in 11/16 patients (69%) with schizoaffective disorder. A surprising finding was that 4/16 (25%) schizoaffective disorder patients were positive for the ABR profiling test for ADHD. Conclusion: With the ABR profiling test a minority of patients with schizoaffective disorder tested positive for schizophrenia. In contrast a majority (85%) of patients with schizophrenia in a previous study tested positive. These preliminary results leave us ignorant whether schizoaffective disorder should be regarded as a schizophrenia-like disorder or a psychotic mood disorder and add to the questions regarding the validity of this diagnostic entity. However, the ABR profiling method is still in its infancy and its exploration in a range of psychiatric disorders is warranted.
These authors were able to follow 2588 consecutive patients in Finland who were hospitalized for ... more These authors were able to follow 2588 consecutive patients in Finland who were hospitalized for the first time for schizophrenia between 2000 and 2007. Strikingly, only 58.2% even collected a prescription for the antipsychotic drug within the first 30 days after hospital discharge, and only 45.7% continued taking the drug for 30 days. When patients taking oral medications were compared with those taking depot medications, the rehospitalization rate for the depot group was only one-third that for the oral group. Interestingly, antipsychotic drug use was associated with lower mortality. Not surprisingly, clozapine and olanzapine were again associated with more favorable outcomes. This is excellent confirmation of what we have known for a long time, but this is not yet the accepted practice worldwide.
The 5-HT,,-receptor antagonist WUH-301 (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin) complete... more The 5-HT,,-receptor antagonist WUH-301 (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin) completely antagonized the hypotension and bradycardia induced by (RI = S-OH DPAT t(R)-8-hydroxy-2-(dipropylamino)tetralin) in conscious rats. W-UH-301 alone induced a weak hypertension, which might be due to its 5-HT,,-receptor antagonistic properties. (RI-UH301 induced effects similar to those of (RI-8-OH DPAT, i.e., a short initial phase of hypertension followed by a long-lasting hypotension and bradycardia. Thus, (RI-UH301 behaves as a 5-HT,,-receptor agonist and (S)-UH301 as a 5-HT,,-receptor antagonist, abolishing the effects induced by (RI-8-OH DPAT.
Quality management and quality control of health services have become increasingly important. Cen... more Quality management and quality control of health services have become increasingly important. Central to the concept of quality of care is the consumer's (the patient's) own view of the care provided. UKU (Udvalg for Kliniske Underseøelser), a task force within the Scandinavian Society for Psychopharmacology, has designed a brief consumer satisfaction rating scale, the UKU-ConSat. The UKU-ConSat rating scale was applied in a randomised comparative two-year study of two community-based treatment programs. The study included 84 patients with schizophrenic disorders according to DSM-IV. The major finding was a significantly increased consumer satisfaction with the new community-based program “Integrated Care” in comparison with best-established practice, called “Rational Rehabilitation.” Thus, the new UKU-ConSat rating scale can detect differences, not only for in-patients as has previously been shown, but also between programs in community care settings. By per item analysis it was possible to discriminate between various elements of consumer satisfaction. There were significant correlations between the UKU-ConSat total scores and other clinical outcome domains, viz. symptoms, social function, and patient as well as carer's distress. To conclude, the UKU-ConSat rating scale is suitable for quality management and monitoring of treatment programs in mental health services.
Studies in animals have shown that the rates of synthesis and turnover of catecholamines (CAs), r... more Studies in animals have shown that the rates of synthesis and turnover of catecholamines (CAs), rather than their levels, reflect changes in the functional activity of adrenergic nerves both in the central nervous system (CNS) and periphery (Costa and Neff, 1966; Costa, 1970; Sedvall, Weise and Kopin, 1968). Since a role for CAs has been implied in many physiological and pathological processes in man such as stress, hormone release, temperature regulation, affective disorders, schizophrenia and hypertension, there has been an interest in developing methods to study CA turnover in humans. The techniques which have been successfully utilised in animals can be divided into ‘steady state’ and ‘non-steady state’ methods. The former methods have advantages over the latter in as much as the analysis does not necessarily involve a perturbation of the system. The most common ‘steady state’ methods are: (1) labelling of the CA stores with radioactive amine and following decay; (2) measuring rate of formation of labelled amine after injection or infusion of the labelled precursor amino acid. ‘Non-steady state’ methods usually employ inhibitors of catecholamine synthesis, metabolism or metabolite transport and measure rates of accumulation or disappearance of the CA or metabolite.
Recent progress in a project aiming at developing selective 5-HT1A-receptor agonists and antagoni... more Recent progress in a project aiming at developing selective 5-HT1A-receptor agonists and antagonists is reviewed. A large number of analogues of 8-OH-DPAT has been synthesized, and throughout, we have attempted to prepare enantiopure derivatives. Modifications have been concentrated to the N-alkyl substituents, and substitutions in the C1, C2 and C3-positions. The synthetic strategies and procedures are discussed. A number of interesting observations have been made. Affinity, efficacy and stereoselectivity are modified by the various substitutions. The results have been used to deduce a 3D-model for 5-HT1A-receptor agonists. Recently, Pd-catalyzed reactions have been utilized to prepare a number of pharmacologically interesting analogues of 8-OH-DPAT with various C8-substituents. We have also succeeded to convert the agonist 8-OH-DPAT into an antagonist by introduction of a C5-fluoro substituent, producing (S)-UH-301. The pharmacology of this selective 5-HT1A-receptor antagonist is discussed.
Griffith, 0. R., Marshall, J., Nasmyth, P. A. (1978) Moncada, S., Bunting, S . , Mullane, K., Tho... more Griffith, 0. R., Marshall, J., Nasmyth, P. A. (1978) Moncada, S., Bunting, S . , Mullane, K., Thorogood, Ibid. 64: 416P P., Vane, J. R., Raz, A,, IYeedleman, P. (1977) Hoffman, B. B., DeLean, A,, Wood, C. L., Schocken, D. D., Lefkowitz, R. J. (1979) Life Sci. 24: 1739-1746 Pearce, P. H., Wright, J. M., Egan, C. M., Scrutton, Hsu, C. Y . , Knapp, D. A,, Halushka, P. V. (1979) J. Pharmacol. Exp. Ther. 208: 366-375 Prostaglandins 13: 611-618
The centrally active muscarinic agonist, oxotremorine, elicited an up to 2-fold dose-dependent (0... more The centrally active muscarinic agonist, oxotremorine, elicited an up to 2-fold dose-dependent (0.25-1.5 mg/kg) increase in the activity of tyrosine hydroxylase (TH) in the rat nucleus locus coeruleus (LC) and adrenal medulla. The response occurred in LC after 24 to 48 hours and in adrenal medulla by 4 to 8 hours, peaked in LC at 72 hours and adrenal medulla at 16 to 24 hours and persisted up to 2 weeks in both tissues. In brain the effect appeared confined to cell bodies of noradrenergic neurons. The activity of dopamine beta-hydroxylase increased in adrenal medulla (40%) but not in brain. Immunotitration with anti-TH serum demonstrated that the increase of TH activity in LC is due to increased catalytic activity (activation), whereas in adrenal medulla it is due to a transynaptically mediated accumulation of enzyme protein (induction). Physostigmine (1.0 mg/kg), pilocarpine (25-50 mg/kg) and nicotine (10 mg/kg) increased TH activity in LC and adrenal. We conclude that stimulation of central cholinergic receptors of the muscarinic type results in a delayed and protracted activaiton of TH but not of dopamine beta-hydroxylase in cell bodies of central noradrenergic neurons, and reflexly, to transynaptic induction of TH and dopamine beta-hydroxylase in the adrenal medulla.
The selective 5-hydroxytryptamine (5-HT1A) receptor agonist 8-hydroxy-2-(dipropylamino)tetralin (... more The selective 5-hydroxytryptamine (5-HT1A) receptor agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) induces a large number of pharmacological effects. In the present study we demonstrate that a novel 8-OH-DPAT analog, (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-UH-301], is able to antagonize completely the following (R)-8-OH-DPAT-induced effects in the rat: 1) reduction in brain 5-HT biosynthesis, measured as a decreased 5-hydroxytryptophan-accumulation after decarboxylase inhibition; 2) induction of the 5-HT1A behavior (flat body posture, forepaw treading and hindlimb abduction) in reserpine-pretreated animals; 3) reduction of body temperature; 4) inhibition of the cage-leaving response; and 5) reduction of 5-hydroxytryptophan- and quipazine-induced wet dog shakes. In addition, (S)-UH-301 reverses the 5-HT-induced inhibition of the forskolin stimulated cyclic AMP production in rat hippocampus without producing any effects per se in this assay. It is shown that high doses of (S)-UH-301 decrease rat brain biosynthesis of dopamine. These and previous data indicate that (S)-UH-301 also is a weakly potent dopamine-receptor agonist, but with a lower affinity for D2 as compared to 5-HT1A receptors. Thus, the data suggest that (S)-UH-301 is a 5-HT1A-receptor antagonist without intrinsic activity. Therefore, it is likely that (S)-UH-301 will become a valuable pharmacological tool in future 5-HT research.
Objective: The aim of the study was to assess whether the auditory brainstem response (ABR) profi... more Objective: The aim of the study was to assess whether the auditory brainstem response (ABR) profiling test for schizophrenia would recognize schizoaffective disorder patients as schizophrenia or not. Method: Male and female schizoaffective disorder patients (n=16) from the psychosis unit at Uppsala University Hospital were investigated. Coded sets of randomized ABR recordings intermingled with patients with schizophrenia, adult attention-deficit hyperactivity disorder (ADHD) and healthy controls, were analyzed by an independent party blinded to clinical diagnoses. Results: The ABR profiling test for schizophrenia was positive in 5/16 patients (31%) and negative in 11/16 patients (69%) with schizoaffective disorder. A surprising finding was that 4/16 (25%) schizoaffective disorder patients were positive for the ABR profiling test for ADHD. Conclusion: With the ABR profiling test a minority of patients with schizoaffective disorder tested positive for schizophrenia. In contrast a majority (85%) of patients with schizophrenia in a previous study tested positive. These preliminary results leave us ignorant whether schizoaffective disorder should be regarded as a schizophrenia-like disorder or a psychotic mood disorder and add to the questions regarding the validity of this diagnostic entity. However, the ABR profiling method is still in its infancy and its exploration in a range of psychiatric disorders is warranted.
These authors were able to follow 2588 consecutive patients in Finland who were hospitalized for ... more These authors were able to follow 2588 consecutive patients in Finland who were hospitalized for the first time for schizophrenia between 2000 and 2007. Strikingly, only 58.2% even collected a prescription for the antipsychotic drug within the first 30 days after hospital discharge, and only 45.7% continued taking the drug for 30 days. When patients taking oral medications were compared with those taking depot medications, the rehospitalization rate for the depot group was only one-third that for the oral group. Interestingly, antipsychotic drug use was associated with lower mortality. Not surprisingly, clozapine and olanzapine were again associated with more favorable outcomes. This is excellent confirmation of what we have known for a long time, but this is not yet the accepted practice worldwide.
The 5-HT,,-receptor antagonist WUH-301 (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin) complete... more The 5-HT,,-receptor antagonist WUH-301 (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin) completely antagonized the hypotension and bradycardia induced by (RI = S-OH DPAT t(R)-8-hydroxy-2-(dipropylamino)tetralin) in conscious rats. W-UH-301 alone induced a weak hypertension, which might be due to its 5-HT,,-receptor antagonistic properties. (RI-UH301 induced effects similar to those of (RI-8-OH DPAT, i.e., a short initial phase of hypertension followed by a long-lasting hypotension and bradycardia. Thus, (RI-UH301 behaves as a 5-HT,,-receptor agonist and (S)-UH301 as a 5-HT,,-receptor antagonist, abolishing the effects induced by (RI-8-OH DPAT.
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