Bipolar disorder is a chronic illness, defined by a succession of depressive and/or manic periods... more Bipolar disorder is a chronic illness, defined by a succession of depressive and/or manic periods separated by free intervals. Its evolution with aging is marked by a high suicide mortality rate. Bipolar disorders raise the question of their evolution when the age of the subject, in particular with regard to their frequency, their clinical characteristics, their prognosis and their management. The evolution of bipolar disorder with aging poses several difficulties in clinical practice due to its underestimated frequency and its misleading presentation and in particular by the presence of sometimes significant cognitive alterations leading sometimes to dementia.
Human Psychopharmacology: Clinical and Experimental, 1987
Eighteen normal volunteers with no sleep difficulties were given psychological tests and asked to... more Eighteen normal volunteers with no sleep difficulties were given psychological tests and asked to fill out a self-evaluation questionnaire 11 h after administration of a hypnotic drug, nitrazepam 5 rng or temazepam 20 mg (in the form of soft gelatin capsules), which was compared to a placebo. Subjects received all three treatments at 1-week intervals, with the administration sequence determined by drawing lots. The tests used were the images test, the digitlsymbol substitution test (DSST), choice reaction time and critical fusion frequency. The two benzodiazepines proved to be efficient hypnotics, improving sleep induction and quality, but nitrazepam caused residual effects, as evidenced by difficult awakening and modified behaviour in the morning, as well as disturbed performance during DSST.
Treating the signs and symptoms of anxiety is an everyday challenge in clinical practice. When ch... more Treating the signs and symptoms of anxiety is an everyday challenge in clinical practice. When choosing between treatment options, anxiety needs to be understood in the situational, psychiatric, and biological context in which it arises. Etifoxine, a nonbenzodiazepine anxiolytic drug belonging to the benzoxazine class, is an effective treatment for anxiety in response to a stressful situation. In the present review, we focused on several aspects of the cerebral and somatic biological mechanisms involved in anxiety and investigated the extent to which etifoxine's mode of action can explain its anxiolytic activity. Its two mechanisms of action are the modulation of GABAergic neurotransmission and neurosteroid synthesis. Recent data suggest that the molecule possesses neuroprotective, neuroplastic, and anti-inflammatory properties. Etifoxine was first shown to be an effective anxiolytic in patients in clinical studies comparing it with clobazam, sulpiride, and placebo. Randomized controlled studies have demonstrated its anxiolytic efficacy in patients with adjustment disorders (ADs) with anxiety, showing it to be superior to buspirone and comparable to lorazepam and phenazepam, with a greater number of markedly improved responders and a better therapeutic index. Etifoxine's noninferiority to alprazolam has also been demonstrated in a comparative trial. Significantly less rebound anxiety was observed after abrupt cessation of etifoxine compared with lorazepam or alprazolam. Consistent with this finding, etifoxine appears to have a very low dependence potential. Unlike lorazepam, it has no effect on psychomotor performance, vigilance, or free recall. Severe adverse events are in general rare. Skin and subcutaneous disorders are the most frequently reported, but these generally resolve after drug cessation. Taken together, its dual mechanisms of action in anxiety and the positive data yielded by clinical trials support the use of etifoxine for treating the anxiety signs and symptoms of individuals with ADs.
Antidepressants regardless of the mechanism of action can cure only 70% of depressed patients. Th... more Antidepressants regardless of the mechanism of action can cure only 70% of depressed patients. There is therefore a category of depression that is called resistant. The co-administration of antidepressants of a different nature can alleviate this deficit. However, it seems necessary to develop active drugs in the resistant depression to develop animal models or even experimental strategies. The purpose of this chapter is to suggest ways to develop new drugs that may be effective in the treatment of resistant depression. Animal models of depression have been developed with a focus on those likely to demonstrate useful drugs in resistant depression or associations. Genetic or pharmacological leads are also mentioned.
Alcohol use disorder or alcoholism is characterized by uncontrollable alcohol use and intoxicatio... more Alcohol use disorder or alcoholism is characterized by uncontrollable alcohol use and intoxication, as well as a heightened state of anxiety after alcohol withdrawal. Ethanol-associated stimuli also drive the urge to drink by means of classical conditioning. Alcoholism has been considered a dopamine (DA) dysregulation syndrome that involves the activity of the central amygdala circuitry of anxiety. Cholecystokinin (CCK) is the most abundant neuropeptide in the mammal brain, where it activates two receptors, CCK1 and CCK2. Genetic evidence relates CCK1 receptors to alcoholism in humans. CCK2 activity has been associated with the onset of human anxiety. CCK modulates DA release in the nucleus accumbens (NAc) and it is expressed in the γ-aminobutyric acid (GABA)-expressing basket interneurons in the cerebral cortex. CCK interacts with serotonin (5-HT) neurotransmission through 5-HT3 receptors to regulate mesocorticolimbic pathways and with GABA to attenuate anxiety in the amygdala. Finally, CCK stimulates the release of orexins and oxytocin in the hypothalamus, two relevant hypothalamic neuropeptides involved in signaling satiety for ethanol and well-being respectively. Given the "dimmer-switch" function of endogenous CCK in the neurotransmission by 5-HT, DA, GABA, and glutamate in normal and pathological behaviors (Ballaz and Bourin, 2020), we hypothesize that CCK adjusts functioning of the reward and anxiety circuitries altered by ethanol. This review gathers data supporting this hypothesis, and suggests mechanisms underlying a role for endogenous CCK in alcoholism.
Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral f... more Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral functions like memory, cognition, and reward through its interactions with the opioid and dopaminergic systems in the limbic system. CCK excites neurons by binding two receptors, CCK1 and CCK2, expressed at low and high levels in the brain, respectively. Historically, CCK2 receptors have been related to the induction of panic attacks in humans. Disturbances in brain CCK expression also underlie the physiopathology of schizophrenia, which is attributed to the modulation by CCK1 receptors of the dopamine flux in the basal striatum. Despite this evidence, neither CCK2 receptor antagonists ameliorate human anxiety nor CCK agonists have consistently shown neuroleptic effects in clinical trials. A neglected aspect of the function of brain CCK is its neuromodulatory role in mental disorders. Interestingly, CCK is expressed in pivotal inhibitory interneurons that sculpt cortical dynamics and the ...
SummaryAs with other drugs it is necessary to look for changes induced by anxiolytics on vital si... more SummaryAs with other drugs it is necessary to look for changes induced by anxiolytics on vital signs, laboratory parameters and adverse events. In return, in a more specific way for anxiolytics, we will look at side effects at the central nervous system level with psychological and physiological battery tests. We will also assess the safety of use of anxiolytics in certain specific conditions, such as overdose or withdrawal and in certain populations such as the elderly, neonates and children. The assessment of safety and side effects, whatever the drug type studied, must come early in the developing process of a drug (phases I, II and III).
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2019
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Consumer Perception of Product Risks and Benefits, 2017
In this chapter, the authors Michel Bourin and Abdeslam Chagroui argue that the nonmedical use an... more In this chapter, the authors Michel Bourin and Abdeslam Chagroui argue that the nonmedical use and abuse of prescription drugs is a serious public health problem. The abuse of certain prescription drugs—opioids, central nervous system (CNS) depressants, and stimulants—can lead to a variety of adverse health effects, including addiction. Prescription drug abuse is not a new problem, but one that deserves renewed attention. So medical drugs abuse is the best researched and understood field, with the highest level of regulation. The present chapter covers a wide range of sources of misuses and abuses including licit or illicit drugs as well as food and beverages and pathological behaviors.
Antagonists of the norepinephrine reuptake and beta-adrenoreceptor agonists are potent, at once, ... more Antagonists of the norepinephrine reuptake and beta-adrenoreceptor agonists are potent, at once, on the three following tests: antagonism of hypothermia induced by reserpine, oxotremorine and apomorphine. 2-Carboxy-4-isopropenyl-3-pyrrolidine-acetic acid (kainic acid), which is a powerful stimulant of the neurons and a destroyer of the dopaminergic neurons, has been used in these tests to show if it is possible to antagonize hypothermia induced by different substances. The results obtained show that kainic acid is potent on these three tests, thus providing evidence that it is a stimulant of norepinephrine neurons as well as serotoninergic neurons, even if it is peripherically injected.
Depression is an incapacitating disease which needs appropriate treatment. This article reviews t... more Depression is an incapacitating disease which needs appropriate treatment. This article reviews the pharmacology of antidepressant drugs and the future perspectives of treating mood disorders such as depression. The foremost theory for explaining the biological basis of depression has been the monoamine hypothesis. Depression is due to a deficiency in one or other biogenic monoamines (serotonin, 5-HT; noradrenaline, NA; dopamine, DA). Antidepressant drugs are therefore classified according to their ability to improve monoaminergic transmission. Since this first theory, other explanations based on abnormal function of monoamine receptors or associated with impaired signalling pathways have been suggested. Notable progress has been accomplished in the treatment of major depressive disorders with new compounds recently discovered (selective serotonin reuptake inhibitors: SSRI; serotonin noradrenaline reuptake inhibitors: SNRI). Behavioural, electrophysiological and microdialysis studie...
Human Psychopharmacology: Clinical and Experimental, 1988
Bupropion, a novel antidepressant drug, is known to be a moderate hepatic metabolism‐inducer in r... more Bupropion, a novel antidepressant drug, is known to be a moderate hepatic metabolism‐inducer in rodents at high doses but not in young human volunteers. Eleven elderly depressed patients (mean age 76·9 ± 8·7 years) entered in the study and received 100 mg of bupropion t.i.d. for 28 days. An antipyrine test was performed before and at day 28 of therapy. Antipyrine was taken orally (15 mg/kg) at 8 a.m. and blood samples were drawn at 11 a.m., 2, 5, and 8 p.m. Plasma levels were assayed using a GLC method. Results show a slight but significant increase of apparent clearance (+30 per cent) and decrease in the half‐life (–14 per cent) of antipyrine. Difference between these results and previous results in young volunteers might be explained by the usual decrease of hepatic function described in elderly patients. Bupropion can be considered in elderly people as a slight hepatic enzyme‐inducer.
Bipolar disorder is a chronic illness, defined by a succession of depressive and/or manic periods... more Bipolar disorder is a chronic illness, defined by a succession of depressive and/or manic periods separated by free intervals. Its evolution with aging is marked by a high suicide mortality rate. Bipolar disorders raise the question of their evolution when the age of the subject, in particular with regard to their frequency, their clinical characteristics, their prognosis and their management. The evolution of bipolar disorder with aging poses several difficulties in clinical practice due to its underestimated frequency and its misleading presentation and in particular by the presence of sometimes significant cognitive alterations leading sometimes to dementia.
Human Psychopharmacology: Clinical and Experimental, 1987
Eighteen normal volunteers with no sleep difficulties were given psychological tests and asked to... more Eighteen normal volunteers with no sleep difficulties were given psychological tests and asked to fill out a self-evaluation questionnaire 11 h after administration of a hypnotic drug, nitrazepam 5 rng or temazepam 20 mg (in the form of soft gelatin capsules), which was compared to a placebo. Subjects received all three treatments at 1-week intervals, with the administration sequence determined by drawing lots. The tests used were the images test, the digitlsymbol substitution test (DSST), choice reaction time and critical fusion frequency. The two benzodiazepines proved to be efficient hypnotics, improving sleep induction and quality, but nitrazepam caused residual effects, as evidenced by difficult awakening and modified behaviour in the morning, as well as disturbed performance during DSST.
Treating the signs and symptoms of anxiety is an everyday challenge in clinical practice. When ch... more Treating the signs and symptoms of anxiety is an everyday challenge in clinical practice. When choosing between treatment options, anxiety needs to be understood in the situational, psychiatric, and biological context in which it arises. Etifoxine, a nonbenzodiazepine anxiolytic drug belonging to the benzoxazine class, is an effective treatment for anxiety in response to a stressful situation. In the present review, we focused on several aspects of the cerebral and somatic biological mechanisms involved in anxiety and investigated the extent to which etifoxine's mode of action can explain its anxiolytic activity. Its two mechanisms of action are the modulation of GABAergic neurotransmission and neurosteroid synthesis. Recent data suggest that the molecule possesses neuroprotective, neuroplastic, and anti-inflammatory properties. Etifoxine was first shown to be an effective anxiolytic in patients in clinical studies comparing it with clobazam, sulpiride, and placebo. Randomized controlled studies have demonstrated its anxiolytic efficacy in patients with adjustment disorders (ADs) with anxiety, showing it to be superior to buspirone and comparable to lorazepam and phenazepam, with a greater number of markedly improved responders and a better therapeutic index. Etifoxine's noninferiority to alprazolam has also been demonstrated in a comparative trial. Significantly less rebound anxiety was observed after abrupt cessation of etifoxine compared with lorazepam or alprazolam. Consistent with this finding, etifoxine appears to have a very low dependence potential. Unlike lorazepam, it has no effect on psychomotor performance, vigilance, or free recall. Severe adverse events are in general rare. Skin and subcutaneous disorders are the most frequently reported, but these generally resolve after drug cessation. Taken together, its dual mechanisms of action in anxiety and the positive data yielded by clinical trials support the use of etifoxine for treating the anxiety signs and symptoms of individuals with ADs.
Antidepressants regardless of the mechanism of action can cure only 70% of depressed patients. Th... more Antidepressants regardless of the mechanism of action can cure only 70% of depressed patients. There is therefore a category of depression that is called resistant. The co-administration of antidepressants of a different nature can alleviate this deficit. However, it seems necessary to develop active drugs in the resistant depression to develop animal models or even experimental strategies. The purpose of this chapter is to suggest ways to develop new drugs that may be effective in the treatment of resistant depression. Animal models of depression have been developed with a focus on those likely to demonstrate useful drugs in resistant depression or associations. Genetic or pharmacological leads are also mentioned.
Alcohol use disorder or alcoholism is characterized by uncontrollable alcohol use and intoxicatio... more Alcohol use disorder or alcoholism is characterized by uncontrollable alcohol use and intoxication, as well as a heightened state of anxiety after alcohol withdrawal. Ethanol-associated stimuli also drive the urge to drink by means of classical conditioning. Alcoholism has been considered a dopamine (DA) dysregulation syndrome that involves the activity of the central amygdala circuitry of anxiety. Cholecystokinin (CCK) is the most abundant neuropeptide in the mammal brain, where it activates two receptors, CCK1 and CCK2. Genetic evidence relates CCK1 receptors to alcoholism in humans. CCK2 activity has been associated with the onset of human anxiety. CCK modulates DA release in the nucleus accumbens (NAc) and it is expressed in the γ-aminobutyric acid (GABA)-expressing basket interneurons in the cerebral cortex. CCK interacts with serotonin (5-HT) neurotransmission through 5-HT3 receptors to regulate mesocorticolimbic pathways and with GABA to attenuate anxiety in the amygdala. Finally, CCK stimulates the release of orexins and oxytocin in the hypothalamus, two relevant hypothalamic neuropeptides involved in signaling satiety for ethanol and well-being respectively. Given the "dimmer-switch" function of endogenous CCK in the neurotransmission by 5-HT, DA, GABA, and glutamate in normal and pathological behaviors (Ballaz and Bourin, 2020), we hypothesize that CCK adjusts functioning of the reward and anxiety circuitries altered by ethanol. This review gathers data supporting this hypothesis, and suggests mechanisms underlying a role for endogenous CCK in alcoholism.
Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral f... more Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral functions like memory, cognition, and reward through its interactions with the opioid and dopaminergic systems in the limbic system. CCK excites neurons by binding two receptors, CCK1 and CCK2, expressed at low and high levels in the brain, respectively. Historically, CCK2 receptors have been related to the induction of panic attacks in humans. Disturbances in brain CCK expression also underlie the physiopathology of schizophrenia, which is attributed to the modulation by CCK1 receptors of the dopamine flux in the basal striatum. Despite this evidence, neither CCK2 receptor antagonists ameliorate human anxiety nor CCK agonists have consistently shown neuroleptic effects in clinical trials. A neglected aspect of the function of brain CCK is its neuromodulatory role in mental disorders. Interestingly, CCK is expressed in pivotal inhibitory interneurons that sculpt cortical dynamics and the ...
SummaryAs with other drugs it is necessary to look for changes induced by anxiolytics on vital si... more SummaryAs with other drugs it is necessary to look for changes induced by anxiolytics on vital signs, laboratory parameters and adverse events. In return, in a more specific way for anxiolytics, we will look at side effects at the central nervous system level with psychological and physiological battery tests. We will also assess the safety of use of anxiolytics in certain specific conditions, such as overdose or withdrawal and in certain populations such as the elderly, neonates and children. The assessment of safety and side effects, whatever the drug type studied, must come early in the developing process of a drug (phases I, II and III).
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2019
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Consumer Perception of Product Risks and Benefits, 2017
In this chapter, the authors Michel Bourin and Abdeslam Chagroui argue that the nonmedical use an... more In this chapter, the authors Michel Bourin and Abdeslam Chagroui argue that the nonmedical use and abuse of prescription drugs is a serious public health problem. The abuse of certain prescription drugs—opioids, central nervous system (CNS) depressants, and stimulants—can lead to a variety of adverse health effects, including addiction. Prescription drug abuse is not a new problem, but one that deserves renewed attention. So medical drugs abuse is the best researched and understood field, with the highest level of regulation. The present chapter covers a wide range of sources of misuses and abuses including licit or illicit drugs as well as food and beverages and pathological behaviors.
Antagonists of the norepinephrine reuptake and beta-adrenoreceptor agonists are potent, at once, ... more Antagonists of the norepinephrine reuptake and beta-adrenoreceptor agonists are potent, at once, on the three following tests: antagonism of hypothermia induced by reserpine, oxotremorine and apomorphine. 2-Carboxy-4-isopropenyl-3-pyrrolidine-acetic acid (kainic acid), which is a powerful stimulant of the neurons and a destroyer of the dopaminergic neurons, has been used in these tests to show if it is possible to antagonize hypothermia induced by different substances. The results obtained show that kainic acid is potent on these three tests, thus providing evidence that it is a stimulant of norepinephrine neurons as well as serotoninergic neurons, even if it is peripherically injected.
Depression is an incapacitating disease which needs appropriate treatment. This article reviews t... more Depression is an incapacitating disease which needs appropriate treatment. This article reviews the pharmacology of antidepressant drugs and the future perspectives of treating mood disorders such as depression. The foremost theory for explaining the biological basis of depression has been the monoamine hypothesis. Depression is due to a deficiency in one or other biogenic monoamines (serotonin, 5-HT; noradrenaline, NA; dopamine, DA). Antidepressant drugs are therefore classified according to their ability to improve monoaminergic transmission. Since this first theory, other explanations based on abnormal function of monoamine receptors or associated with impaired signalling pathways have been suggested. Notable progress has been accomplished in the treatment of major depressive disorders with new compounds recently discovered (selective serotonin reuptake inhibitors: SSRI; serotonin noradrenaline reuptake inhibitors: SNRI). Behavioural, electrophysiological and microdialysis studie...
Human Psychopharmacology: Clinical and Experimental, 1988
Bupropion, a novel antidepressant drug, is known to be a moderate hepatic metabolism‐inducer in r... more Bupropion, a novel antidepressant drug, is known to be a moderate hepatic metabolism‐inducer in rodents at high doses but not in young human volunteers. Eleven elderly depressed patients (mean age 76·9 ± 8·7 years) entered in the study and received 100 mg of bupropion t.i.d. for 28 days. An antipyrine test was performed before and at day 28 of therapy. Antipyrine was taken orally (15 mg/kg) at 8 a.m. and blood samples were drawn at 11 a.m., 2, 5, and 8 p.m. Plasma levels were assayed using a GLC method. Results show a slight but significant increase of apparent clearance (+30 per cent) and decrease in the half‐life (–14 per cent) of antipyrine. Difference between these results and previous results in young volunteers might be explained by the usual decrease of hepatic function described in elderly patients. Bupropion can be considered in elderly people as a slight hepatic enzyme‐inducer.
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