- Email: [email protected]
Pharmacological approaches predicting antidepressant or anxiolytic activities: What is common and what is different
S78
(s.o9.04(
S.09 Treatment of the comorbidity of anxious and depressioe states
Pharmacological approaches predicting antidepressant or anxiolytic activities: What is common and what is different
B. Olivier. Department of Psychopharmacology, RudolfMagnus Institute for Neuroscience, Faculty of Pharmacy, Utrecht Unioersity, Sorbonnelaan 36, 3584 Utrecht, The Netherlands Classically, anxiolytic activity is modulated via activation of the benzodiazepine (BZ) receptor at the GABAA-Benzodiazepine receptor complex. Agonists at these receptors exert powerful anxiolytic activity in humans and in animals. Antidepressant activity on the other hand, is primarily linked to modulation of monoaminergic systems, especially the serotonergic and noradrenergic ones. Classical tricyclic antidepressants and the newer specific uptake inhibitors, all share the property of either enhancing serotonin or noradrenaline concentration in the brain. In general, BZ receptor agonists are not active in animal models of depression, whereas some antidepressants show activity in some animal models of anxiety. This may indicate that the GABAA-BZ receptor systems in the brain are primarily involved in anxiety processes, whereas monoaminergic systems may fi11filla more general, moderating role in both anxiety and depression. Several animal models are available to detect anxiolytic and antidepressant properties of psychotropic drugs. In animal models of anxiety, BZ-receptor agonists are always active, illustrating their powerful capacities as anxiolytic agents. In an animal model we have developed (Molewijk et al. 1995), the conditioned ultrasonic vocalization paradigm (AW) in adult rats, we found a remarkable insensitivity of the model for benzodiazepine receptor ligands. Classical BZ-agonists like diazepam and chlordiazepoxide were inactive, similar to partial agonistic (bretazenil) or BZ-receptor subtype selective agonists (alpidem, zolpidem). Remarkably, only alprazolam inhibited ultrasonic calling suggesting the AW-paradigm as a putative model for panic disorders, because IBZagonists are not considered as first choice therapy, except alprazolam. The validity of the AW-model for panic disorder was further supported by the finding that imipramine and the SSRIs, but not desimipramine and maprotiline, were also active, similar to clinical practice. The AW-paradigm seems sensitive to some qualities of the BZreceptor system and also to some aspects of monoaminergic systems. 5HT~Areceptor agonists appeared very active in this paradigm, suggesting a strong anxiolytic (antipanic) potential. ~-HTIA receptor agonists are also antidepressant, indicating that anxiolytic and antidepressant qualities can be present in one pharmacological mechanism. Recently, we found (unpublished) that dopamine agonists were active in the AW, and also in two models of depression, the differential reinforcement of low rates of responding (DRL725) and the forced swim test. Although DA-agonists induce several motor effects, which may disturb behaviour considerably, low doses of especially dopamine D2-agonists may have potent anxiolytic and antidepressant activity It therefore seems that not only NA and 5-HT, but also DA systems are intrinsically involved in the modulation of anxiety and depression. Could it be that the GABAA-BZ receptor system, is a primary CNS system for anxiety that is modulated by various other systems, especially monoaminergic systems or are there separate systems, activated under special conditions? There is ample evidence that the first hypothesis is the more likely one, in that activity of the GABAA-BZ system can be modulated by monoaminergic systems in various ways. Experiments aiming at this kind of questions could be supported by studying tranagenic or knock-out animals, in which via manipulation of the DNA genes are added or knocked out in the genome. Various benzodiazepine receptor subunit knock-outs have been made, but most of them appeared lethal, supporting a very fimdamental role for BZreceptors (and GABAA) in life. Knock-out mice for various monoaminergic receptors have been made and appear vital. We presently study 5HTIB receptor knock-out mice on various aspects of anxiety, depression, impulsivity, feeding and circadian rhythmicity. 5-HTln KO mice appear more impulsive than their wildtype counterparts; they react more to
mild stimuli measured in general activity, bodytemperature and heart rate. Their response to a stressor appears normal measured by stress hormones or c-fos activation in the CNS. Remarkably, the 5-HTia KO’s have higher bodyweight, food and water intake than the wildtypes but are not obese. We presently start work on the ~-HT~A receptor knock-out mouse, which appears more anxious than the wildtypes. Whether such knock-out mice have deviances in several other aspects of anxiety and depression is under investigation, but preliminary data look promising. In conclusion: several pharmacologic approaches share anxiolytic and antidepressant properties, whereas some are strictly bound to anxiety only (GABAA-BZ system). This presumably has to with the organization of these systems in the brain. A core mechanism (GABAA-BZ receptors?) for anxiety seems to be modulated by various other mechanism, including monoaminergic ones. Whether a core mechanism for mood (depression) can be depicted is unclear yet. If such a mechanism exists, again various modulating systems impinge on it, again with a prominent role for MA-systems. References
[l] MolewijkHE, Van der Poe1AM, Mos J, Van der Heyden JAM, Olivier B. Conditioned ultrasonic distress vocalisations in adult male rats as a behavioural paradigm for screening anti-panic drugs. Psychopharmacology 1995; 117: 3240.
[s.o9.051
The clinical interrelation between anxiety and mood disorders
M. Linden. Department of Psychiatry, Freie Unioersitiit Berlin, Berlin, Germany Diagnosticand Conceptual Issues: Depression and/or anxiety can be interrelated on a symptom level, a syndrome level or a nosological level (Helmchen & Linden 1986). Depressed mood in the sense of oppressed or a kind of non-mood or anhedonia has to be discriminated fimn anxiety as a feeling of apprehension with the expectation of threat as well as from many other forms of bad mood such as dysphoria, grief, displeasure, unhappiness or ill-humour. On a syndromal level the same symptoms can be seen in depressive or anxiety disorders. Therefore it is difficult to differentiate between depression and anxiety scales e.g. by factor or cluster analysis. On the nosological level either a hierarchical or a comorbidity paradigm is used. The hierarchical approach, which is the classical diagnostic procedure coming from Jaspers, assumes that certain disorders include others so that only the primary diagnosis will be made. In this view organic disorders include psychotic symptoms, psychotic disorders also depressive symptoms, and depressive disorders anxiety The comorbidity approach allows to apply algorithms for any disorder on the basis of all present symptoms irrespective of how many and what kind of diagnostic criteria are fullfilled in the end. Additional complexity arises if not only comorbidity with specified disorders but also with “subthreshold disorders” is allowed (Angst 1997). A further diagnostic problem is that symptoms can present differently depending on the severity of the present episode but also depending on the point in the development of the present episode, e.g at the beginning or at it’s maximum. Finally, under a longitudial perspective type, quality, and severity of disorders can switch from one to another either in a sequential or in an unsystematic way (Helmchen & Linden 1986). Frequency of Cooccurrence and Comorbidity: Cooccurence of depression and anxiety on a symptom level is frequent. Over 95% of patients with depressive disorders have at least one symptom of anxiety, and 20% to 65% of patients with anxiety do also experience lowered mood. Comorbidity in the sense that full criteria for both types of disorders are fullfilled is somewhat lower but still of considerable size. In an international study of WHO on Psychological Problems in General Health Care (Sartorius et al 1996, Linden et al 1996) 7.9% of practice attenders were found to suffer from GAD and 10.4% from a current depressive episode. 4.8% were suffering from GAD alone, 7.3% from depression alone and 3.2% fullfilled criteria for both at the same time.
(s.o9.04(
S.09 Treatment of the comorbidity of anxious and depressioe states
Pharmacological approaches predicting antidepressant or anxiolytic activities: What is common and what is different
B. Olivier. Department of Psychopharmacology, RudolfMagnus Institute for Neuroscience, Faculty of Pharmacy, Utrecht Unioersity, Sorbonnelaan 36, 3584 Utrecht, The Netherlands Classically, anxiolytic activity is modulated via activation of the benzodiazepine (BZ) receptor at the GABAA-Benzodiazepine receptor complex. Agonists at these receptors exert powerful anxiolytic activity in humans and in animals. Antidepressant activity on the other hand, is primarily linked to modulation of monoaminergic systems, especially the serotonergic and noradrenergic ones. Classical tricyclic antidepressants and the newer specific uptake inhibitors, all share the property of either enhancing serotonin or noradrenaline concentration in the brain. In general, BZ receptor agonists are not active in animal models of depression, whereas some antidepressants show activity in some animal models of anxiety. This may indicate that the GABAA-BZ receptor systems in the brain are primarily involved in anxiety processes, whereas monoaminergic systems may fi11filla more general, moderating role in both anxiety and depression. Several animal models are available to detect anxiolytic and antidepressant properties of psychotropic drugs. In animal models of anxiety, BZ-receptor agonists are always active, illustrating their powerful capacities as anxiolytic agents. In an animal model we have developed (Molewijk et al. 1995), the conditioned ultrasonic vocalization paradigm (AW) in adult rats, we found a remarkable insensitivity of the model for benzodiazepine receptor ligands. Classical BZ-agonists like diazepam and chlordiazepoxide were inactive, similar to partial agonistic (bretazenil) or BZ-receptor subtype selective agonists (alpidem, zolpidem). Remarkably, only alprazolam inhibited ultrasonic calling suggesting the AW-paradigm as a putative model for panic disorders, because IBZagonists are not considered as first choice therapy, except alprazolam. The validity of the AW-model for panic disorder was further supported by the finding that imipramine and the SSRIs, but not desimipramine and maprotiline, were also active, similar to clinical practice. The AW-paradigm seems sensitive to some qualities of the BZreceptor system and also to some aspects of monoaminergic systems. 5HT~Areceptor agonists appeared very active in this paradigm, suggesting a strong anxiolytic (antipanic) potential. ~-HTIA receptor agonists are also antidepressant, indicating that anxiolytic and antidepressant qualities can be present in one pharmacological mechanism. Recently, we found (unpublished) that dopamine agonists were active in the AW, and also in two models of depression, the differential reinforcement of low rates of responding (DRL725) and the forced swim test. Although DA-agonists induce several motor effects, which may disturb behaviour considerably, low doses of especially dopamine D2-agonists may have potent anxiolytic and antidepressant activity It therefore seems that not only NA and 5-HT, but also DA systems are intrinsically involved in the modulation of anxiety and depression. Could it be that the GABAA-BZ receptor system, is a primary CNS system for anxiety that is modulated by various other systems, especially monoaminergic systems or are there separate systems, activated under special conditions? There is ample evidence that the first hypothesis is the more likely one, in that activity of the GABAA-BZ system can be modulated by monoaminergic systems in various ways. Experiments aiming at this kind of questions could be supported by studying tranagenic or knock-out animals, in which via manipulation of the DNA genes are added or knocked out in the genome. Various benzodiazepine receptor subunit knock-outs have been made, but most of them appeared lethal, supporting a very fimdamental role for BZreceptors (and GABAA) in life. Knock-out mice for various monoaminergic receptors have been made and appear vital. We presently study 5HTIB receptor knock-out mice on various aspects of anxiety, depression, impulsivity, feeding and circadian rhythmicity. 5-HTln KO mice appear more impulsive than their wildtype counterparts; they react more to
mild stimuli measured in general activity, bodytemperature and heart rate. Their response to a stressor appears normal measured by stress hormones or c-fos activation in the CNS. Remarkably, the 5-HTia KO’s have higher bodyweight, food and water intake than the wildtypes but are not obese. We presently start work on the ~-HT~A receptor knock-out mouse, which appears more anxious than the wildtypes. Whether such knock-out mice have deviances in several other aspects of anxiety and depression is under investigation, but preliminary data look promising. In conclusion: several pharmacologic approaches share anxiolytic and antidepressant properties, whereas some are strictly bound to anxiety only (GABAA-BZ system). This presumably has to with the organization of these systems in the brain. A core mechanism (GABAA-BZ receptors?) for anxiety seems to be modulated by various other mechanism, including monoaminergic ones. Whether a core mechanism for mood (depression) can be depicted is unclear yet. If such a mechanism exists, again various modulating systems impinge on it, again with a prominent role for MA-systems. References
[l] MolewijkHE, Van der Poe1AM, Mos J, Van der Heyden JAM, Olivier B. Conditioned ultrasonic distress vocalisations in adult male rats as a behavioural paradigm for screening anti-panic drugs. Psychopharmacology 1995; 117: 3240.
[s.o9.051
The clinical interrelation between anxiety and mood disorders
M. Linden. Department of Psychiatry, Freie Unioersitiit Berlin, Berlin, Germany Diagnosticand Conceptual Issues: Depression and/or anxiety can be interrelated on a symptom level, a syndrome level or a nosological level (Helmchen & Linden 1986). Depressed mood in the sense of oppressed or a kind of non-mood or anhedonia has to be discriminated fimn anxiety as a feeling of apprehension with the expectation of threat as well as from many other forms of bad mood such as dysphoria, grief, displeasure, unhappiness or ill-humour. On a syndromal level the same symptoms can be seen in depressive or anxiety disorders. Therefore it is difficult to differentiate between depression and anxiety scales e.g. by factor or cluster analysis. On the nosological level either a hierarchical or a comorbidity paradigm is used. The hierarchical approach, which is the classical diagnostic procedure coming from Jaspers, assumes that certain disorders include others so that only the primary diagnosis will be made. In this view organic disorders include psychotic symptoms, psychotic disorders also depressive symptoms, and depressive disorders anxiety The comorbidity approach allows to apply algorithms for any disorder on the basis of all present symptoms irrespective of how many and what kind of diagnostic criteria are fullfilled in the end. Additional complexity arises if not only comorbidity with specified disorders but also with “subthreshold disorders” is allowed (Angst 1997). A further diagnostic problem is that symptoms can present differently depending on the severity of the present episode but also depending on the point in the development of the present episode, e.g at the beginning or at it’s maximum. Finally, under a longitudial perspective type, quality, and severity of disorders can switch from one to another either in a sequential or in an unsystematic way (Helmchen & Linden 1986). Frequency of Cooccurrence and Comorbidity: Cooccurence of depression and anxiety on a symptom level is frequent. Over 95% of patients with depressive disorders have at least one symptom of anxiety, and 20% to 65% of patients with anxiety do also experience lowered mood. Comorbidity in the sense that full criteria for both types of disorders are fullfilled is somewhat lower but still of considerable size. In an international study of WHO on Psychological Problems in General Health Care (Sartorius et al 1996, Linden et al 1996) 7.9% of practice attenders were found to suffer from GAD and 10.4% from a current depressive episode. 4.8% were suffering from GAD alone, 7.3% from depression alone and 3.2% fullfilled criteria for both at the same time.