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P.1.046 Transcranial magnetic stimulation in combination with antidepressant drugs in major depression: Preliminary results
Poster Sessions
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some parameters of the hormonal and neurotransmitter systems. We examined 112 mentally and somatically healthy persons matched in sex and age as a comparative group for immunobiological investigation. Results: We found that in the process of alprozolam therapy in patients positive dynamics occurred in the number and ratio of the populations of immunocompetent cells (helpers/inductors, natural killers); indices of the humoral immunity and phagocytosis in the process of the therapy practically did not change. At the same time, a peculiarity of the therapy with bromazepam was the activation of phagocytosis. We revealed decrease of cortisone concentration and increase of ACTH concentration in blood serum of patients along with improvement of clinical symptoms in the process of the therapy with anxiolytics. We detected various immunotropic traits of the SSRIs. Fluoxetine possessed considerable immunostimulating action. Some immunosuppressive action was revealed in citaloprarr~ insignificant decrease of the group of immunocompetent cells - CD3 +, CD16 +, CD72 + - were observed. An intermediate position according to immunological properties between these preparations was occupied by zololt - increases in the content of CD4 ÷, CD16 ÷ and t-ILA-Dr+ were observed, with a small decrease of leukocytes and CD2+-lymphocytes. On the indices of phagocytic activity all the preparations possessed one-directional moderate-suppressive action. Numbers of lymphocytes having receptors to serotonin and noradrenalin that were increased before the beginning of the therapy decreased up to the level of control, at the same time SSRI therapy did not exert substantial influence on the ACTH dynamics. Conclusions: Psychotropic drugs (tranquilisers of the benzodiazepine group and serotonin re-uptake inhibitors) act on the exchange of neurotransmitters and hormones which leads to alteration of central mechanisms of regulation of immunity functioning on the side of nervous, hormonal and neuromediatory systems.
[l] Semke V., Vetlugina T., Nevidimova T., Ivanova S., Bokhan N. 2003. Clinical Psychoneuroimmunology, 300pp [in Russian].
has been more extensively applied, mainly as adjunctive treatment for drug resistant patients. This randomised, double-blind, placebo-controlled study investigated the efficacy and tolerability of high frequency repetitive transcranial magnetic stimulation in combination with different pharmacological antidepressant treatments in depressed patients. Methods: Right-handed patients, consecutively admitted to the Mood Disorders Center of our Department, were included in the study. Alter the procedure has been fully explained, informed written consent was obtained. All patients were suffering from a major depressive episode (minimum Hamilton Rating Scale for Depression score of 24) without psychotic features. The patients were treated with either SSRIs or SNRI (sertraline up to 200mg/day or escitalopram up to 20mg/day, or venlafaxine up to 300mg/day) and sham or active stimulation according to a computer generated random list. Exclusion criteria were: age younger than 18 years and older than 75 years, history of seizures or neurological illnesses, severe medical conditions that could interfere with the clinical evaluation, pregnancy or mental retardation. Patients bearing pacemakers, mobile metal implants, implanted medical pumps or metal clips placed inside the skull, were also excluded in accordance with the safety criteria for TMS. All patients underwent 10 sessions of stimulation over a 2-week period (Monday to Friday). The 3 groups were as follows: in Group 1 all patients were on sertraline and received sham or active TMS, in Group 2 patients were on escitalopram and received sham or active TMS; the patients of Group 3 were on venlafaxine and received sham or active stimulation. Response was defined as a ) 5 0 % decrease in the HAM-D total score from baseline, and remission was defined as a HAM-D total score ~<8 for at least three consecutive weeks. Results: Statistical difference was found regarding both the presence/absence of TMS and among pharmacological treatments. Conclusion: Our finding suggests that TMS may be effective in accelerating antidepressant drugs response in depressed patients.
•]
References
References
Transcranial magnetic stimulation in combination with antidepressant drugs in major depression: preliminary results
D. Rossini, A. Lucca, R. Zanardi, E. Smeraldi. Department
of Psychiatry, School of Medicine, Vita-Salute University San Raffaele, Ha Stamira D'Ancona 20, Milan, Italy Objectives: Major depression is the mental disorder in which repetitive transcranial magnetic stimulation (rTMS)
[1] Berman, R.M. et al., 2000. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol. Psychiatr 47, 332-337. [2] Fitzgerald, RB. et al., 2003. Transcranial magnetic stimulation in the treatment of depression: a doubleblind, placebo-controlled trial. Arch. Gen. Psychiatr 60, 1002-1008.
Poster Sessions [3] Loo, C.K. et al., 1999. Double-blind controlled investigation of transcranial magnetic stimulation for the treatment of resistant major depression. Am. J. Psychiatr 156, 946--948.
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increased following olanzapine injection in all studied brain structures. The results obtained allow us to suggest that CCI drugs can modulate the effects of neuroleptics on the activity of DA- and 5-HT-ergic neurotransmitter systems.
Psychotic disorders and antlpsychotlcs
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Effects of olanzapine and verapamil combination on the neurotransmit. ter content in Wistar rat brain structures
V.B. Narkevich. Zalcusov State Institute of Pharmacology, Russian Academy of Medical Sciences, 125315, Moscow, Russia Despite the major advances in the treatment of schizophrenia during the recent decades, neuroleptic drugs currently used in clinics have many disadvantages including such side-effects as parkinsonism and tardive dyskinesia. Considering this, the development of potent antipsychotic drugs lacking these faults is still of crucial importance. Another mainline of modem neuropsychopharmacology is the search for substances able to correct the side-effects ofneuroleptics. There is a growing body of evidence suggesting that calcium channel inhibitors (CCI) may be beneficial in the treatment of some central nervous system disorders such as stroke, epilepsy, depression, schizophrenia, etc. Anyway, existing data on interaction between neuroleptics and CCI are rather controversial. So, the main goal of the present work was to study the effects of a combination of the atypical antipsychotic olanzapine (5mg/kg i.p.) and verapamil (2 mg/kg i.p), the most commonly used CCI drug, on main neurotransmitters and their metabolite content in Wistar rat brain structures. The brain structures [frontal cortex (FC), hippocampus (Hp), hypothalamus (HTh), nucleus accumbens (NAt) and striatum (St)] were extracted on ice, frozen and stored in liquid nitrogen. The levels of monoamines and their metabolites were measured by high performance liquid chromatography with electrochemical detection (I-IPLC/ED) techniques. A rise of norepinephrine content in all studied brain structures has been detected. The dopamine (DA) levels were found to increase in FC and St and to diminish in Hp. A rise ofDA metabolite dioxyphenylacetic acid (DOPAC) content was shown in FC and St whereas the concentration of homovanillic acid (HVA), another DA metabolite, did not change in all the structures studied. The most dramatic increases in serotonin (5-HT) content were demonstrated in FC and St. It was found that verapamil induced statistically significant decreases in DA and 5-HT turnover
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Conformationally constrained analogues of antipsychotic dipeptide N-caproylL.prolyI.L.tyrosine methyl ester
A.N. Ignashin, N.I. Zaitseva, M.V. Retunskaya. Zakusoo State Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow, 125315, Russia Dipeptide N-caproyl-L-prolyl-L-tyrosine methyl ester (later named dilept) was designed as an analogue of active site of neuropeptide neurotensin [1]. Dilept has clinical potential as a perspective antipsychotic agent [2]. In the range of antidopamine tests it was active at EDs0 0.45mg/kg, i.p. [3]. The aim of this study was to investigate the structure-activity relationships in order to clarify the bioactive conformation of dilept. Proline residue essential for conformation behaviour of dilept was substituted for the conformationally mobile glycine residue. The modification affecting both proline and N-caproyl space was performed using the dibenzoazipine structure. Restriction of tyrosine residue conformational space was realized by methylation of--carbon atom. Pharmacological activity of synthesized dilept analogues was studied in the test o f inhibition o fapomorphineinduced climbing. It was found that modification of proline residue resulted in the decrease of antidopamine effect. The C-methyl analogue of dilept has neurolepticlike activity even more pronounced than that of dilept (EDs0 0.22mg/kg, i.p.). These results show that the C-methylation of tyrosine residue is most likely the bioactive conformation of dilept.
References [1] Gudasheva T.A. et al., 1998, Design of N-acylprolyltyrosine "tripeptoid" analogues ofneurotensin as potential atypical antipsychotic agents. L Med. Chem. 41(3), 284-290. [2] Seredenin S.B. et al., 1997, Substituted prolyltyrosines with psychotropic activity. Russian Patent No. 2091390. [3] Ostrovskaya R.U. et al., Neurotensine tripeptoid analogue dilept combines the antipsychotic activity with the positive mnemotropic effect. Exp. Clinical Pharm., in press (2004).
s128
some parameters of the hormonal and neurotransmitter systems. We examined 112 mentally and somatically healthy persons matched in sex and age as a comparative group for immunobiological investigation. Results: We found that in the process of alprozolam therapy in patients positive dynamics occurred in the number and ratio of the populations of immunocompetent cells (helpers/inductors, natural killers); indices of the humoral immunity and phagocytosis in the process of the therapy practically did not change. At the same time, a peculiarity of the therapy with bromazepam was the activation of phagocytosis. We revealed decrease of cortisone concentration and increase of ACTH concentration in blood serum of patients along with improvement of clinical symptoms in the process of the therapy with anxiolytics. We detected various immunotropic traits of the SSRIs. Fluoxetine possessed considerable immunostimulating action. Some immunosuppressive action was revealed in citaloprarr~ insignificant decrease of the group of immunocompetent cells - CD3 +, CD16 +, CD72 + - were observed. An intermediate position according to immunological properties between these preparations was occupied by zololt - increases in the content of CD4 ÷, CD16 ÷ and t-ILA-Dr+ were observed, with a small decrease of leukocytes and CD2+-lymphocytes. On the indices of phagocytic activity all the preparations possessed one-directional moderate-suppressive action. Numbers of lymphocytes having receptors to serotonin and noradrenalin that were increased before the beginning of the therapy decreased up to the level of control, at the same time SSRI therapy did not exert substantial influence on the ACTH dynamics. Conclusions: Psychotropic drugs (tranquilisers of the benzodiazepine group and serotonin re-uptake inhibitors) act on the exchange of neurotransmitters and hormones which leads to alteration of central mechanisms of regulation of immunity functioning on the side of nervous, hormonal and neuromediatory systems.
[l] Semke V., Vetlugina T., Nevidimova T., Ivanova S., Bokhan N. 2003. Clinical Psychoneuroimmunology, 300pp [in Russian].
has been more extensively applied, mainly as adjunctive treatment for drug resistant patients. This randomised, double-blind, placebo-controlled study investigated the efficacy and tolerability of high frequency repetitive transcranial magnetic stimulation in combination with different pharmacological antidepressant treatments in depressed patients. Methods: Right-handed patients, consecutively admitted to the Mood Disorders Center of our Department, were included in the study. Alter the procedure has been fully explained, informed written consent was obtained. All patients were suffering from a major depressive episode (minimum Hamilton Rating Scale for Depression score of 24) without psychotic features. The patients were treated with either SSRIs or SNRI (sertraline up to 200mg/day or escitalopram up to 20mg/day, or venlafaxine up to 300mg/day) and sham or active stimulation according to a computer generated random list. Exclusion criteria were: age younger than 18 years and older than 75 years, history of seizures or neurological illnesses, severe medical conditions that could interfere with the clinical evaluation, pregnancy or mental retardation. Patients bearing pacemakers, mobile metal implants, implanted medical pumps or metal clips placed inside the skull, were also excluded in accordance with the safety criteria for TMS. All patients underwent 10 sessions of stimulation over a 2-week period (Monday to Friday). The 3 groups were as follows: in Group 1 all patients were on sertraline and received sham or active TMS, in Group 2 patients were on escitalopram and received sham or active TMS; the patients of Group 3 were on venlafaxine and received sham or active stimulation. Response was defined as a ) 5 0 % decrease in the HAM-D total score from baseline, and remission was defined as a HAM-D total score ~<8 for at least three consecutive weeks. Results: Statistical difference was found regarding both the presence/absence of TMS and among pharmacological treatments. Conclusion: Our finding suggests that TMS may be effective in accelerating antidepressant drugs response in depressed patients.
•]
References
References
Transcranial magnetic stimulation in combination with antidepressant drugs in major depression: preliminary results
D. Rossini, A. Lucca, R. Zanardi, E. Smeraldi. Department
of Psychiatry, School of Medicine, Vita-Salute University San Raffaele, Ha Stamira D'Ancona 20, Milan, Italy Objectives: Major depression is the mental disorder in which repetitive transcranial magnetic stimulation (rTMS)
[1] Berman, R.M. et al., 2000. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol. Psychiatr 47, 332-337. [2] Fitzgerald, RB. et al., 2003. Transcranial magnetic stimulation in the treatment of depression: a doubleblind, placebo-controlled trial. Arch. Gen. Psychiatr 60, 1002-1008.
Poster Sessions [3] Loo, C.K. et al., 1999. Double-blind controlled investigation of transcranial magnetic stimulation for the treatment of resistant major depression. Am. J. Psychiatr 156, 946--948.
s129
increased following olanzapine injection in all studied brain structures. The results obtained allow us to suggest that CCI drugs can modulate the effects of neuroleptics on the activity of DA- and 5-HT-ergic neurotransmitter systems.
Psychotic disorders and antlpsychotlcs
•
Effects of olanzapine and verapamil combination on the neurotransmit. ter content in Wistar rat brain structures
V.B. Narkevich. Zalcusov State Institute of Pharmacology, Russian Academy of Medical Sciences, 125315, Moscow, Russia Despite the major advances in the treatment of schizophrenia during the recent decades, neuroleptic drugs currently used in clinics have many disadvantages including such side-effects as parkinsonism and tardive dyskinesia. Considering this, the development of potent antipsychotic drugs lacking these faults is still of crucial importance. Another mainline of modem neuropsychopharmacology is the search for substances able to correct the side-effects ofneuroleptics. There is a growing body of evidence suggesting that calcium channel inhibitors (CCI) may be beneficial in the treatment of some central nervous system disorders such as stroke, epilepsy, depression, schizophrenia, etc. Anyway, existing data on interaction between neuroleptics and CCI are rather controversial. So, the main goal of the present work was to study the effects of a combination of the atypical antipsychotic olanzapine (5mg/kg i.p.) and verapamil (2 mg/kg i.p), the most commonly used CCI drug, on main neurotransmitters and their metabolite content in Wistar rat brain structures. The brain structures [frontal cortex (FC), hippocampus (Hp), hypothalamus (HTh), nucleus accumbens (NAt) and striatum (St)] were extracted on ice, frozen and stored in liquid nitrogen. The levels of monoamines and their metabolites were measured by high performance liquid chromatography with electrochemical detection (I-IPLC/ED) techniques. A rise of norepinephrine content in all studied brain structures has been detected. The dopamine (DA) levels were found to increase in FC and St and to diminish in Hp. A rise ofDA metabolite dioxyphenylacetic acid (DOPAC) content was shown in FC and St whereas the concentration of homovanillic acid (HVA), another DA metabolite, did not change in all the structures studied. The most dramatic increases in serotonin (5-HT) content were demonstrated in FC and St. It was found that verapamil induced statistically significant decreases in DA and 5-HT turnover
•
Conformationally constrained analogues of antipsychotic dipeptide N-caproylL.prolyI.L.tyrosine methyl ester
A.N. Ignashin, N.I. Zaitseva, M.V. Retunskaya. Zakusoo State Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow, 125315, Russia Dipeptide N-caproyl-L-prolyl-L-tyrosine methyl ester (later named dilept) was designed as an analogue of active site of neuropeptide neurotensin [1]. Dilept has clinical potential as a perspective antipsychotic agent [2]. In the range of antidopamine tests it was active at EDs0 0.45mg/kg, i.p. [3]. The aim of this study was to investigate the structure-activity relationships in order to clarify the bioactive conformation of dilept. Proline residue essential for conformation behaviour of dilept was substituted for the conformationally mobile glycine residue. The modification affecting both proline and N-caproyl space was performed using the dibenzoazipine structure. Restriction of tyrosine residue conformational space was realized by methylation of--carbon atom. Pharmacological activity of synthesized dilept analogues was studied in the test o f inhibition o fapomorphineinduced climbing. It was found that modification of proline residue resulted in the decrease of antidopamine effect. The C-methyl analogue of dilept has neurolepticlike activity even more pronounced than that of dilept (EDs0 0.22mg/kg, i.p.). These results show that the C-methylation of tyrosine residue is most likely the bioactive conformation of dilept.
References [1] Gudasheva T.A. et al., 1998, Design of N-acylprolyltyrosine "tripeptoid" analogues ofneurotensin as potential atypical antipsychotic agents. L Med. Chem. 41(3), 284-290. [2] Seredenin S.B. et al., 1997, Substituted prolyltyrosines with psychotropic activity. Russian Patent No. 2091390. [3] Ostrovskaya R.U. et al., Neurotensine tripeptoid analogue dilept combines the antipsychotic activity with the positive mnemotropic effect. Exp. Clinical Pharm., in press (2004).