Pharmacology can contribute in four ways to our understanding and to the management of resistant ... more Pharmacology can contribute in four ways to our understanding and to the management of resistant depression: 1) Dosage: some antidepressants have an inverted-U dose-response curve, i.e. the response disappears when dosage is increased. In man, dose-response relationships are not well established because the curves are obtained with groups of patients and they reflect an overall mean rather than the reality of each individual patient. 2) Secondary regulatory adaptive mechanism such as: down regulation of beta, 5-HT2, alpha-2 receptors--increased reactivity of 5-HT1A, alpha-1 and dopaminergic systems. Defective development of these mechanisms is thought to originate resistance in certain cases, which could therefore be corrected more or less specifically by adding thyroid hormone, lithium, an alpha-2 agonist or even by switching to a 5-HT1A agonist or a dopaminergic drug. 3) Biological resistance factors: it has been shown in the rat that hypothyroidism, diabetes, weight loss cause a ...
Progress in neuro-psychopharmacology & biological psychiatry, 1989
1. The physiological and behavioral effects of T3 and corresponding plasma T3 levels were studied... more 1. The physiological and behavioral effects of T3 and corresponding plasma T3 levels were studied in mice. 2. On the tests performed (antagonism of apomorphine- and oxotremorine-induced hypothermia, potentiation of yohimbine toxicity, L-5-HTP-induced head twitches and the learned-helplessness paradigm), T3 was active after subchronic treatment (1 injection per day for 3 days, ending 24 hours before testing). 3. In these tests T3 exhibited the same profile as antidepressant drugs in rodents. 4. The similar activity of beta-agonists in these tests and the ability of T3 to potentiate the effect of clenbuterol agree with the hypothesis that T3 can induce beta-adrenergic hypersensitivity. 5. Under the present experimental conditions these effects were obtained with doses of T3 which did not induce hyper-triiodothyroninemia. Thus, the lowest doses significantly affecting apomorphine- and oxotremorine-induced hypothermia were respectively .008 and .032 mg/kg/day. 6. Doses as low as .032 mg...
Triiodothyroacetic acid (TA3) is a natural thyroid analogue which possesses some of the propertie... more Triiodothyroacetic acid (TA3) is a natural thyroid analogue which possesses some of the properties of triiodothyronine (T3). In particular, it has an inhibitory effect on the thyreotropic axis, but its peripheral effects are reduced. Given the activity of T3 on psychopharmacological models of depression in rodents, we investigated the effects of TA3 on some pharmacological and behavioral tests in mice. TA3 antagonized apomorphine- and oxotremorine-induced hypothermia, potentiated yohimbine-induced toxicity and L-5-hydroxy-tryptophan-induced head twitches, but did not affect forced swimming-induced immobility or reserpine-induced hypothermia. Thus, TA3 was effective on the same psychopharmacological tests which have previously been used to demonstrate the antidepressant-like effects of T3. Moreover, TA3 under the same experimental conditions as T3 has little effect on the metabolic clearance rate parameters, and might, therefore, be preferable to T3 for clinical use in depression.
Using the learned helplessness model of depression in rats, the present study undertook to invest... more Using the learned helplessness model of depression in rats, the present study undertook to investigate the possibility of an impaired response to antidepressant drugs in diabetic animals. Experimental diabetes was induced by three intraperitoneal (IP) injections of streptozotocin (37.5, 37.5, 50 mg/kg, three days apart), four weeks before behavioral testing. Diabetic and non-diabetic rats were first exposed to 60 inescapable shocks. Forty-eight hours later and over three consecutive days, they were subjected to daily shuttle-box sessions for assessment of escape failures (helpless behavior). Twice daily (IP) injection of clomipramine (24 mg/kg), desipramine (24 mg/kg), imipramine (32 mg/kg) or clenbuterol (0.75 mg/kg) prevented escape deficits in the non-diabetic but not in the diabetic rats. However, this prevention was made possible in the diabetic rats by increasing the duration of the antidepressant treatment. Moreover, one week of insulin therapy restored operant escape responding to both the tricyclics and a beta-agonist. The inefficacy of clenbuterol (a central beta-agonist) in reversing helpless behavior in diabetic rats, along with the observation that triiodothyronine (T3) supplementation also restored the response to imipramine in the diabetic rats, suggests that thyroid-mediated alterations of central noradrenergic function might be a critical factor in the resistance or delayed response to antidepressants in experimental diabetes. These animal findings raise the possibility of a similar resistance to conventional antidepressants in depressed diabetic patients.
The major problem in predicting clinical efficacy from animal experimental results and phase I da... more The major problem in predicting clinical efficacy from animal experimental results and phase I data is the lack of resemblance between the models used and the clinical condition. This problem is complicated by the diversity of the potential mechanisms of action of new compounds. A further question is whether Phase I studies should be used as predictors of clinical efficacy at all. Should they be used simply for determining pharmacologically active dose ranges and tolerance? If used as predictors should drug development stop if negative results are obtained? These questions were not resolved. It was nonetheless suggested that some human models (e.g. scopolamine-induced amnesia, hypoxia-induced performance deficits) were indeed potential predictors of clinical response and, in addition, were analogous to similar models in animals. On the other hand characterisation of quantified EEG (QEEG) profiles remained controversial.
Milnacipran (Ixel) is a new antidepressant with essentially equal potency for inhibiting the reup... more Milnacipran (Ixel) is a new antidepressant with essentially equal potency for inhibiting the reuptake of both serotonin and noradrenaline, with no affinity for any neurotransmitter receptor studied. A review of the studies comparing milnacipran, placebo and active comparator antidepressants provides clear-cut evidence of its efficacy in both severe and moderate depression in hospitalized and community settings. Meta-analyses of the original data of controlled trials involving 1032 patients, comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs), show that milnacipran provides antidepressant efficacy similar to that of imipramine and significantly superior to that of the SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of the tricyclic antidepressants (TCAs) with fewer cholinergic side-effects. The tolerability of milnacipran was comparable to that of the SSRIs, with a higher incidence of dysuria with milnacipran, and a higher frequency of nausea and anxiety with the SSRIs. Milnacipran is a new therapeutic option in depression, which offers a clinical efficacy in the range of the TCAs combined with a tolerability equivalent to that of the SSRIs.
The Brief Psychiatric Rating Scale (BPRS) anxiety/depression subscore has been used to assess aff... more The Brief Psychiatric Rating Scale (BPRS) anxiety/depression subscore has been used to assess affective symptoms in three studies (n = 612) comparing amisulpride (400-800 mg/day, n = 339) with haloperidol (15-20 mg/day, n = 160) and risperidone (8 mg/day, n = 113) in the treatment of acute exacerbations of schizophrenia. At endpoint, the mean improvement in the anxiety/depression subscore showed a significant (P = 0.011) difference in favour of amisulpride (5.6+/-6.1) compared with haloperidol (4.4+/-5.5) and risperidone (3.7+/-4.7). Amisulpride provided a significantly greater improvement compared both to haloperidol and risperidone in more severely depressed patients (BPRS anxiety/depression subscore > or = 16 at baseline, P = 0.001). This significant advantage in favour of amisulpride is seen from the 2nd week of treatment.
The effect of a non selective and a cardio-selective beta-blocker on basal and exercise-stimulate... more The effect of a non selective and a cardio-selective beta-blocker on basal and exercise-stimulated plasma atrial natriuretic peptide concentrations in healthy volunteers has been studied. Nine healthy volunteers received single oral doses of 5 mg tertatolol, 100 mg atenolol or placebo, at one week intervals, in a double blind cross over trial. At rest plasma atrial natriuretic peptide, aldosterone, antidiuretic hormone and cyclic GMP concentrations and plasma renin activity were not modified by the treatments. During exercise plasma atrial natriuretic peptide concentrations were significantly increased by each treatment, the increment being significantly greater on beta-blockers than on placebo. The rise in atrial natriuretic peptide was 72% after placebo (from 24 to 42 pg/ml), 184% after atenolol (from 30 to 86 pg/ml), and 183% after tertatolol (from 34 to 95 pg/ml), respectively. Thus, the study has shown that in healthy subjects the plasma natriuretic peptide concentration is increased by exercise and that the increase is considerably and equally potentiated by selective and non selective beta-adrenoceptor blockade. The effect may be mainly due to a reduction in ventricular contractility with an increase in atrial pressure. The beta-blockers did not influence the resting plasma atrial natriuretic peptide levels, which suggests that in healthy subjects basal atrial natriuretic peptide secretion is not controlled via beta-receptors.
Pharmacology can contribute in four ways to our understanding and to the management of resistant ... more Pharmacology can contribute in four ways to our understanding and to the management of resistant depression: 1) Dosage: some antidepressants have an inverted-U dose-response curve, i.e. the response disappears when dosage is increased. In man, dose-response relationships are not well established because the curves are obtained with groups of patients and they reflect an overall mean rather than the reality of each individual patient. 2) Secondary regulatory adaptive mechanism such as: down regulation of beta, 5-HT2, alpha-2 receptors--increased reactivity of 5-HT1A, alpha-1 and dopaminergic systems. Defective development of these mechanisms is thought to originate resistance in certain cases, which could therefore be corrected more or less specifically by adding thyroid hormone, lithium, an alpha-2 agonist or even by switching to a 5-HT1A agonist or a dopaminergic drug. 3) Biological resistance factors: it has been shown in the rat that hypothyroidism, diabetes, weight loss cause a ...
Progress in neuro-psychopharmacology & biological psychiatry, 1989
1. The physiological and behavioral effects of T3 and corresponding plasma T3 levels were studied... more 1. The physiological and behavioral effects of T3 and corresponding plasma T3 levels were studied in mice. 2. On the tests performed (antagonism of apomorphine- and oxotremorine-induced hypothermia, potentiation of yohimbine toxicity, L-5-HTP-induced head twitches and the learned-helplessness paradigm), T3 was active after subchronic treatment (1 injection per day for 3 days, ending 24 hours before testing). 3. In these tests T3 exhibited the same profile as antidepressant drugs in rodents. 4. The similar activity of beta-agonists in these tests and the ability of T3 to potentiate the effect of clenbuterol agree with the hypothesis that T3 can induce beta-adrenergic hypersensitivity. 5. Under the present experimental conditions these effects were obtained with doses of T3 which did not induce hyper-triiodothyroninemia. Thus, the lowest doses significantly affecting apomorphine- and oxotremorine-induced hypothermia were respectively .008 and .032 mg/kg/day. 6. Doses as low as .032 mg...
Triiodothyroacetic acid (TA3) is a natural thyroid analogue which possesses some of the propertie... more Triiodothyroacetic acid (TA3) is a natural thyroid analogue which possesses some of the properties of triiodothyronine (T3). In particular, it has an inhibitory effect on the thyreotropic axis, but its peripheral effects are reduced. Given the activity of T3 on psychopharmacological models of depression in rodents, we investigated the effects of TA3 on some pharmacological and behavioral tests in mice. TA3 antagonized apomorphine- and oxotremorine-induced hypothermia, potentiated yohimbine-induced toxicity and L-5-hydroxy-tryptophan-induced head twitches, but did not affect forced swimming-induced immobility or reserpine-induced hypothermia. Thus, TA3 was effective on the same psychopharmacological tests which have previously been used to demonstrate the antidepressant-like effects of T3. Moreover, TA3 under the same experimental conditions as T3 has little effect on the metabolic clearance rate parameters, and might, therefore, be preferable to T3 for clinical use in depression.
Using the learned helplessness model of depression in rats, the present study undertook to invest... more Using the learned helplessness model of depression in rats, the present study undertook to investigate the possibility of an impaired response to antidepressant drugs in diabetic animals. Experimental diabetes was induced by three intraperitoneal (IP) injections of streptozotocin (37.5, 37.5, 50 mg/kg, three days apart), four weeks before behavioral testing. Diabetic and non-diabetic rats were first exposed to 60 inescapable shocks. Forty-eight hours later and over three consecutive days, they were subjected to daily shuttle-box sessions for assessment of escape failures (helpless behavior). Twice daily (IP) injection of clomipramine (24 mg/kg), desipramine (24 mg/kg), imipramine (32 mg/kg) or clenbuterol (0.75 mg/kg) prevented escape deficits in the non-diabetic but not in the diabetic rats. However, this prevention was made possible in the diabetic rats by increasing the duration of the antidepressant treatment. Moreover, one week of insulin therapy restored operant escape responding to both the tricyclics and a beta-agonist. The inefficacy of clenbuterol (a central beta-agonist) in reversing helpless behavior in diabetic rats, along with the observation that triiodothyronine (T3) supplementation also restored the response to imipramine in the diabetic rats, suggests that thyroid-mediated alterations of central noradrenergic function might be a critical factor in the resistance or delayed response to antidepressants in experimental diabetes. These animal findings raise the possibility of a similar resistance to conventional antidepressants in depressed diabetic patients.
The major problem in predicting clinical efficacy from animal experimental results and phase I da... more The major problem in predicting clinical efficacy from animal experimental results and phase I data is the lack of resemblance between the models used and the clinical condition. This problem is complicated by the diversity of the potential mechanisms of action of new compounds. A further question is whether Phase I studies should be used as predictors of clinical efficacy at all. Should they be used simply for determining pharmacologically active dose ranges and tolerance? If used as predictors should drug development stop if negative results are obtained? These questions were not resolved. It was nonetheless suggested that some human models (e.g. scopolamine-induced amnesia, hypoxia-induced performance deficits) were indeed potential predictors of clinical response and, in addition, were analogous to similar models in animals. On the other hand characterisation of quantified EEG (QEEG) profiles remained controversial.
Milnacipran (Ixel) is a new antidepressant with essentially equal potency for inhibiting the reup... more Milnacipran (Ixel) is a new antidepressant with essentially equal potency for inhibiting the reuptake of both serotonin and noradrenaline, with no affinity for any neurotransmitter receptor studied. A review of the studies comparing milnacipran, placebo and active comparator antidepressants provides clear-cut evidence of its efficacy in both severe and moderate depression in hospitalized and community settings. Meta-analyses of the original data of controlled trials involving 1032 patients, comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs), show that milnacipran provides antidepressant efficacy similar to that of imipramine and significantly superior to that of the SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of the tricyclic antidepressants (TCAs) with fewer cholinergic side-effects. The tolerability of milnacipran was comparable to that of the SSRIs, with a higher incidence of dysuria with milnacipran, and a higher frequency of nausea and anxiety with the SSRIs. Milnacipran is a new therapeutic option in depression, which offers a clinical efficacy in the range of the TCAs combined with a tolerability equivalent to that of the SSRIs.
The Brief Psychiatric Rating Scale (BPRS) anxiety/depression subscore has been used to assess aff... more The Brief Psychiatric Rating Scale (BPRS) anxiety/depression subscore has been used to assess affective symptoms in three studies (n = 612) comparing amisulpride (400-800 mg/day, n = 339) with haloperidol (15-20 mg/day, n = 160) and risperidone (8 mg/day, n = 113) in the treatment of acute exacerbations of schizophrenia. At endpoint, the mean improvement in the anxiety/depression subscore showed a significant (P = 0.011) difference in favour of amisulpride (5.6+/-6.1) compared with haloperidol (4.4+/-5.5) and risperidone (3.7+/-4.7). Amisulpride provided a significantly greater improvement compared both to haloperidol and risperidone in more severely depressed patients (BPRS anxiety/depression subscore > or = 16 at baseline, P = 0.001). This significant advantage in favour of amisulpride is seen from the 2nd week of treatment.
The effect of a non selective and a cardio-selective beta-blocker on basal and exercise-stimulate... more The effect of a non selective and a cardio-selective beta-blocker on basal and exercise-stimulated plasma atrial natriuretic peptide concentrations in healthy volunteers has been studied. Nine healthy volunteers received single oral doses of 5 mg tertatolol, 100 mg atenolol or placebo, at one week intervals, in a double blind cross over trial. At rest plasma atrial natriuretic peptide, aldosterone, antidiuretic hormone and cyclic GMP concentrations and plasma renin activity were not modified by the treatments. During exercise plasma atrial natriuretic peptide concentrations were significantly increased by each treatment, the increment being significantly greater on beta-blockers than on placebo. The rise in atrial natriuretic peptide was 72% after placebo (from 24 to 42 pg/ml), 184% after atenolol (from 30 to 86 pg/ml), and 183% after tertatolol (from 34 to 95 pg/ml), respectively. Thus, the study has shown that in healthy subjects the plasma natriuretic peptide concentration is increased by exercise and that the increase is considerably and equally potentiated by selective and non selective beta-adrenoceptor blockade. The effect may be mainly due to a reduction in ventricular contractility with an increase in atrial pressure. The beta-blockers did not influence the resting plasma atrial natriuretic peptide levels, which suggests that in healthy subjects basal atrial natriuretic peptide secretion is not controlled via beta-receptors.
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