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Adjunctive therapy in severe depression
54-4
S.02 Treatment of addiction states
mechanism may underlie the efficacy of mirtazapine in severe depression. Also venlafaxine works by two potential mechanisms of action, i.e. the inhibition of reuptake of both SlIT and NE. Further studies are necessary to answer the question. if "dual action" of antidepressant drugs on more than one neurotransmitter system (SHT, NE) has advantages compared to "mono action" on only one system (SSRI) in severe depression.
ated with depression. Studies to date indicate that such patients can be relatively treatment refractory. Whether or not they respond better to tri-iodothyronine or l-thyroxine has yet to be demonstrated in placebo controlledstudies. Nonetheless, it is clear from placebo controlled studies of patients who are antidepressantresistant, that T 3 is a useful strategy in many patients.
References
DeMontigny C, Grunberg F, Mayer A and Deschenes JP. (1981) Lithium induces rapid relief in tricyclic antidepressant drug non-responders. British Journal of Psychiatry. 138, 252-256. Dinan TG and Barry S. (1989) A comparison of electroconvulsive therapy with a combined lithium and tricyclic combination in depressed tricyclic nonresponders. Acta Psychiatrica Scandinavica. 80.97-100. Thakore J and Dinan TG. (1995) Lowering cortisol enhances prolactin responses to d-fenfluramine in major depression. Biological Psychiatry. 37. 364-368.
Brunelle, N.. Burrows, G.D., Jonsson, C.P.B.•Judd, L.L., Kasper, S., Keller, M.B., Kupfer. DJ., Lecrubier, Y., Mendlewicz. J., Montgomery. S.A., Nemeroff, C.B., Preskom, S., Racagni, G. and Rush.AJ . (1995) Critical issues in thetreatment
of affective disorders. Depression 3, 187-198. Kasper. S. (1993) Is severe depression a different illness? The pharmacological evidence. European Neuropsychopbannacology 3, 215-217. Kasper, S. (1995a) Clinical efficacy of mlnazapine: a review of meta-analyses of pooled data. Int. Clin. Psychopharmacology 10(Suppl. 4), 25-35. Kasper, S., Moller, H.1., Montgomery, SA and Zondag, E. (l995b) Antidepressantefficacy in relation 10 itemanalysis andseverity of depression: a placebocontrolled trial offiuvoxamine versus imipramine.lnt. Clin. Psychopharmacology 9 (Suppl. 4), 3-12. Zivkov, M., Roes. K.C.B. and Pols, A.G. (1995) Efficacy of Org 3770 and amitriptyline in patients with major depressive disorder: a meta-analysis. Hum. Psychopharmacology 10(Suppl. 2), 135-145.
I5.01.04 , Adjunctive therapy in severe depression T.G. Dinan. Department ofPsychological Medicine. St Bartholomew's
Hospital, London EC1A 7BE There have been significant strides in the management of depression since the original tricyclic antidepressants were developed in the late 50s and 60s. The major advances have clearly been made in terms of tolerability and safety. The problem of treatment non-response is shared by newer and older antidepressantsalike. Approximately 30% of patients with major depression fail to respond to an adequate dosage and duration of treatment. Whilst there is still some debate as to what constitutes an adequate dosage of antidepressant, there is general agreement that treatment should be for at least six weeks before a patient is definedas a non-responder. The use of lithium augmentation has, in recent years, been popu· larised by DeMontigny and his colleagues (1981). They showed that lithium augmented clomipramine in patients who were refractory to the antidepressant. We have compared the efficacy of this strategy with electroconvulsive therapy in patients with severedepression(Dinanand Barry 1989). Patients were randomly allocated to treatment either with lithium or with electroconvulsive therapy. In both cases, the antidepressant was continued. Outcome in both groups over a four week period was equal, but those patients treated with lithium showed a more rapid response. At the end of week 1, patients treated with lithium in combination with an antidepressant had a lower Hamilton score than those patients treated with electroconvulsive therapy. A number of research groups have focused on the hypothalamicpituitary-adrenal axis as a target for antidepressantaction. A short course of high-dose dexamethasone is reported to have antidepressant action. In patients previously resistant to sertraline or fluoxetine, we added dexamethasone 4 mg daily for three days. The dexamethasone was then discontinued and the patient remained on the antidepressant alone. Such an approach resulted in a significant drop in Hamilton depression scores. Ketoconazole, the antifungal agent, is a potent inhibitor of cortisolsynthesis. We have examined its effectiveness in patients with melancholic depression who had elevated cortisol levels (Thakore & Dinan 1995). In all patients, ketoconazole treatment produced a marked reduction in cortisol. At the same time, in each subject it enhanced serotonergic neurotransmissionas indexed by the d-fenfluramine/prolactin stimulation test. In all cases, subjects showed greater prolactin release in response to d-fenfluramine challenge following ketoconazole treatment than they had at baseline. Overall, ketoconazole treatment produced a significant reduction in Hamilton depression scores. This strategy offers a second means of targeting the hypothalamic-pituitary-adrenal axis in patients who have refractory depression. Grade n hypothyroidism. characterised by elevated TSH levels and normal T4 and T3 levels, can pose significant problems when associ-
References
8.02 Treatment of addiction states
I5.02.01 I Modulation of drug reward by receptor ligands E. Zvartau, A. Bespalov, A. Kuzmin, N. Patkina, S. Semenova.
Department 0/Psychopharmacology. Institute ofPharmacology, Pavlov Medical University. St. Petersburg 197089. Russia A set of experimentshas been completed to study the calcium channels, benzodiazepine and NMDA receptors ligands' efficacy in modulation of drug reward. Reinforcing effects of morphine, cocaine, amphetamine, nicotineand ethanol were shown to be affected by calcium channel modulators of dihydropyridine (DHP) group. DHP calcium channel blockers (CCB) inhibited drug reward as measured by i.v. self-administration (IVSA) and conditioned place preference (CPP) paradigms. whereas calcium channels activator BayK 8644 exhibited the opposite action (cocaine and morphine). Ltype CCB La+++ but not N-type CCB Gd+++ and omega-conotoxin GVIA under i.c.v, administration inhibit cocaineinducedlocomotorstimulation and CPP. It is concluded, that drug reward is sensitive to the normal functional state of L-type calcium channels. Blockade of inward calcium fluxes through slow neuronal channels is tempting to propose is able to prevent long lasting adaptations of second messengersin the CNS to the effects of typical drugs of abuse. Ethanol IVSA was studied in benzodiazepine (BDZ) receptors ligands (Ro 15-1788, Ro 15·4513 and diazepam) pretreated mice. Animals demonstrated bell-shaped dose-response curve with highest IVSA at the 2% concentration. All ligands,except diazepam, decreasedethanol IVSA. The ED50s (mglkg) of drugs were 0.11 (Ro 15-4513, sIc) and 7.55 (Ro 15-1788, sic). The effect of opioid receptors ligands on cocaine IVSA was studied in drug-naive mice. Naloxone (1 mg/kg), but not naloxone-methyl-iodide, and butorphanol ( I mglkg) produced a shift of the concentration-response curve to the right while buprenorphine (0.1 mglkg) and nalbuphine (2 mglkg) shifted the concentration-response curve to the left as compared 10 saline treated animals. U·50488H produced a shift of the curve to the left indicatingthe facilitating influenceon cocaine rewardingeffect. Both the dopamine and the opioid systems are considered [0 playa role in reinforcing properties of cocaine. Interactionbetween these systems has been suggested to form a neural substrate for reward. However, the possibility that dopaminergic and opioid systems operate in independent. parallel, reward mechanisms should not be ruled out. Cooperative interaction of mu and kappa opioid systems is supposedto have special importance. Glutamate receptors are shown to be implicated in various druginduced behaviors. Our data suggested that conditioned [drug} effects may be dependent on the glutamatergic function. Thus, expression of drug- conditioned locomotion and conditioned activation of intracranial self-stimulation (ICSS) were prevented by pretreatment with NMDA receptor antagonists. Moreover, conditioned (learned) components of morphine tolerance to analgesia was abolished by glutamate antagonists. Another major effect of glutamate antagonists is the ability to attenuate the development of dependence, tolerance andlor sensitization to various effects of different psychoactive drugs. Tolerance to morphine analgesic effect, as well as sensitization to ICSS·facilitating properties were effectively blocked by NMDA andlor non·NMDA receptors antagonists. In
S.02 Treatment of addiction states
mechanism may underlie the efficacy of mirtazapine in severe depression. Also venlafaxine works by two potential mechanisms of action, i.e. the inhibition of reuptake of both SlIT and NE. Further studies are necessary to answer the question. if "dual action" of antidepressant drugs on more than one neurotransmitter system (SHT, NE) has advantages compared to "mono action" on only one system (SSRI) in severe depression.
ated with depression. Studies to date indicate that such patients can be relatively treatment refractory. Whether or not they respond better to tri-iodothyronine or l-thyroxine has yet to be demonstrated in placebo controlledstudies. Nonetheless, it is clear from placebo controlled studies of patients who are antidepressantresistant, that T 3 is a useful strategy in many patients.
References
DeMontigny C, Grunberg F, Mayer A and Deschenes JP. (1981) Lithium induces rapid relief in tricyclic antidepressant drug non-responders. British Journal of Psychiatry. 138, 252-256. Dinan TG and Barry S. (1989) A comparison of electroconvulsive therapy with a combined lithium and tricyclic combination in depressed tricyclic nonresponders. Acta Psychiatrica Scandinavica. 80.97-100. Thakore J and Dinan TG. (1995) Lowering cortisol enhances prolactin responses to d-fenfluramine in major depression. Biological Psychiatry. 37. 364-368.
Brunelle, N.. Burrows, G.D., Jonsson, C.P.B.•Judd, L.L., Kasper, S., Keller, M.B., Kupfer. DJ., Lecrubier, Y., Mendlewicz. J., Montgomery. S.A., Nemeroff, C.B., Preskom, S., Racagni, G. and Rush.AJ . (1995) Critical issues in thetreatment
of affective disorders. Depression 3, 187-198. Kasper. S. (1993) Is severe depression a different illness? The pharmacological evidence. European Neuropsychopbannacology 3, 215-217. Kasper, S. (1995a) Clinical efficacy of mlnazapine: a review of meta-analyses of pooled data. Int. Clin. Psychopharmacology 10(Suppl. 4), 25-35. Kasper, S., Moller, H.1., Montgomery, SA and Zondag, E. (l995b) Antidepressantefficacy in relation 10 itemanalysis andseverity of depression: a placebocontrolled trial offiuvoxamine versus imipramine.lnt. Clin. Psychopharmacology 9 (Suppl. 4), 3-12. Zivkov, M., Roes. K.C.B. and Pols, A.G. (1995) Efficacy of Org 3770 and amitriptyline in patients with major depressive disorder: a meta-analysis. Hum. Psychopharmacology 10(Suppl. 2), 135-145.
I5.01.04 , Adjunctive therapy in severe depression T.G. Dinan. Department ofPsychological Medicine. St Bartholomew's
Hospital, London EC1A 7BE There have been significant strides in the management of depression since the original tricyclic antidepressants were developed in the late 50s and 60s. The major advances have clearly been made in terms of tolerability and safety. The problem of treatment non-response is shared by newer and older antidepressantsalike. Approximately 30% of patients with major depression fail to respond to an adequate dosage and duration of treatment. Whilst there is still some debate as to what constitutes an adequate dosage of antidepressant, there is general agreement that treatment should be for at least six weeks before a patient is definedas a non-responder. The use of lithium augmentation has, in recent years, been popu· larised by DeMontigny and his colleagues (1981). They showed that lithium augmented clomipramine in patients who were refractory to the antidepressant. We have compared the efficacy of this strategy with electroconvulsive therapy in patients with severedepression(Dinanand Barry 1989). Patients were randomly allocated to treatment either with lithium or with electroconvulsive therapy. In both cases, the antidepressant was continued. Outcome in both groups over a four week period was equal, but those patients treated with lithium showed a more rapid response. At the end of week 1, patients treated with lithium in combination with an antidepressant had a lower Hamilton score than those patients treated with electroconvulsive therapy. A number of research groups have focused on the hypothalamicpituitary-adrenal axis as a target for antidepressantaction. A short course of high-dose dexamethasone is reported to have antidepressant action. In patients previously resistant to sertraline or fluoxetine, we added dexamethasone 4 mg daily for three days. The dexamethasone was then discontinued and the patient remained on the antidepressant alone. Such an approach resulted in a significant drop in Hamilton depression scores. Ketoconazole, the antifungal agent, is a potent inhibitor of cortisolsynthesis. We have examined its effectiveness in patients with melancholic depression who had elevated cortisol levels (Thakore & Dinan 1995). In all patients, ketoconazole treatment produced a marked reduction in cortisol. At the same time, in each subject it enhanced serotonergic neurotransmissionas indexed by the d-fenfluramine/prolactin stimulation test. In all cases, subjects showed greater prolactin release in response to d-fenfluramine challenge following ketoconazole treatment than they had at baseline. Overall, ketoconazole treatment produced a significant reduction in Hamilton depression scores. This strategy offers a second means of targeting the hypothalamic-pituitary-adrenal axis in patients who have refractory depression. Grade n hypothyroidism. characterised by elevated TSH levels and normal T4 and T3 levels, can pose significant problems when associ-
References
8.02 Treatment of addiction states
I5.02.01 I Modulation of drug reward by receptor ligands E. Zvartau, A. Bespalov, A. Kuzmin, N. Patkina, S. Semenova.
Department 0/Psychopharmacology. Institute ofPharmacology, Pavlov Medical University. St. Petersburg 197089. Russia A set of experimentshas been completed to study the calcium channels, benzodiazepine and NMDA receptors ligands' efficacy in modulation of drug reward. Reinforcing effects of morphine, cocaine, amphetamine, nicotineand ethanol were shown to be affected by calcium channel modulators of dihydropyridine (DHP) group. DHP calcium channel blockers (CCB) inhibited drug reward as measured by i.v. self-administration (IVSA) and conditioned place preference (CPP) paradigms. whereas calcium channels activator BayK 8644 exhibited the opposite action (cocaine and morphine). Ltype CCB La+++ but not N-type CCB Gd+++ and omega-conotoxin GVIA under i.c.v, administration inhibit cocaineinducedlocomotorstimulation and CPP. It is concluded, that drug reward is sensitive to the normal functional state of L-type calcium channels. Blockade of inward calcium fluxes through slow neuronal channels is tempting to propose is able to prevent long lasting adaptations of second messengersin the CNS to the effects of typical drugs of abuse. Ethanol IVSA was studied in benzodiazepine (BDZ) receptors ligands (Ro 15-1788, Ro 15·4513 and diazepam) pretreated mice. Animals demonstrated bell-shaped dose-response curve with highest IVSA at the 2% concentration. All ligands,except diazepam, decreasedethanol IVSA. The ED50s (mglkg) of drugs were 0.11 (Ro 15-4513, sIc) and 7.55 (Ro 15-1788, sic). The effect of opioid receptors ligands on cocaine IVSA was studied in drug-naive mice. Naloxone (1 mg/kg), but not naloxone-methyl-iodide, and butorphanol ( I mglkg) produced a shift of the concentration-response curve to the right while buprenorphine (0.1 mglkg) and nalbuphine (2 mglkg) shifted the concentration-response curve to the left as compared 10 saline treated animals. U·50488H produced a shift of the curve to the left indicatingthe facilitating influenceon cocaine rewardingeffect. Both the dopamine and the opioid systems are considered [0 playa role in reinforcing properties of cocaine. Interactionbetween these systems has been suggested to form a neural substrate for reward. However, the possibility that dopaminergic and opioid systems operate in independent. parallel, reward mechanisms should not be ruled out. Cooperative interaction of mu and kappa opioid systems is supposedto have special importance. Glutamate receptors are shown to be implicated in various druginduced behaviors. Our data suggested that conditioned [drug} effects may be dependent on the glutamatergic function. Thus, expression of drug- conditioned locomotion and conditioned activation of intracranial self-stimulation (ICSS) were prevented by pretreatment with NMDA receptor antagonists. Moreover, conditioned (learned) components of morphine tolerance to analgesia was abolished by glutamate antagonists. Another major effect of glutamate antagonists is the ability to attenuate the development of dependence, tolerance andlor sensitization to various effects of different psychoactive drugs. Tolerance to morphine analgesic effect, as well as sensitization to ICSS·facilitating properties were effectively blocked by NMDA andlor non·NMDA receptors antagonists. In