- Email: [email protected]
S.2.01 Can PTSD be prevented? Strategic interventions in the ‘golden hours’
Symposia [3] Akiskal, H.S., 2007. Targeting suicide prevention to modifiable risk factors: Has bipolar II been overlooked? Acta Psychiat Scand. 116, 395–402.
S.1.05 Depression and general medical condition R. Bunevicius1 ° . 1 Kaunas University of Medicine, Institute of Psychophysiology and Rehabilitation, Palanga, Lithuania Depression often co-exists with physical illnesses, often called as general medical conditions (GMC). Such GMC may precede the depression, may cause it, or may be a consequence of it. Interaction between depression and GMC differs in different persons and different situations and should be evaluated properly. Diagnosing primary depressive disorder it is important to exclude the GMC because it may be responsible for the manifestation of symptoms of depression. A variety of medical conditions can cause depression, including degenerating neurological diseases, such as Alzheimer’s disease; vitamin deficiencies; endocrine diseases, such as thyroid dysfunction or adrenal dysfunction; stroke or tumor of the frontal part of the brain; and certain viral infections, such as mononucleosis. Certain medications, such as steroids or substance abuse, may also cause depression. In all these cases GMC is considered having direct physiological effects causing depressive disorder. Several clinical features suggest a medical origin of mood symptoms including late onset of the initial depressive episode, atypical presentation of mood disorder, treatment resistance or unusual response to treatment. Depressive disorder directly related with GMC is called mood disorder due to GMC in the DSM-IV classification or organic mood (depressive) disorder in the ICD-10 classification. The first step managing organic mood disorder is treatment of the GMC. Successful treatment of the GMC usually results in the resolution of symptoms of depression. This confirms causal role of the GMC for manifestation of depressive disorder. When symptoms of depression remain after cure of the GMC diagnosis of organic mood disorder should be re-evaluated and standard antidepressive treatment should be considered. An example of such an interaction between mood disorder and GMC may be an association between depression and thyroid disorder. It is well recognized that thyroid dysfunction, hypothyroidism and hyperthyroidism, is associated with mood or anxiety disorders. Majority of patients with Graves’ hyperthyroidism have at least one mood or anxiety disorder. Compensation of thyroid dysfunction results in restoration of normal mood in
S111
majority of patients; however, in significant proportion of patients symptoms of anxiety or depression remain even after restoration of euthyroidism [1], suggesting that mental dysfunction may be related with mechanisms, other than thyroid hormone secretion. Thyroid autoimmune process per se may be a mechanism responsible for the manifestation of symptoms of anxiety and/or depression [2]. Another important mechanism connecting GMC and depression is low triiodothyronine (T3) syndrome, reported in serious medical conditions as well as in depression. It was demonstrated by our group [3] that depressed patients with coronary artery disease, especially men, as compared to euthymic patients with coronary artery disease, demonstrate lower T3 concentrations, suggesting that low T3 syndrome may be a causal factor of depression in patients with coronary artery disease. There is no data does compensation of low T3 syndrome result in improvement in symptoms of depression in patients with coronary artery disease or in patients with other GMC. It may be concluded that clinical as well as subclinical, thyroid dysfunction, including patients with low T3 syndrome, or autoimmune involvement of the thyroid axis even with mormal functioning, may be related with mood disorders, including depression. Studies on impact of compensation of subclinical thyroid dysfunction, including low T3 syndrome, on symptoms of depression are needed. Reference(s) [1] Bunevicius R., Prange A.J. Jr. 2006 Psychiatric manifestations of Graves’ hyperthyroidism: pathophysiology and treatment options. CNS Drugs 20:897– 909. [2] Bunevicius R., Peceliuniene J., Mickuviene N. et al. 2007 Mood and thyroid immunity assessed by ultrasonographic imaging in a primary health care. J Affect Disord 97:85−90. [3] Bunevicius R., Varoneckas G., Prange A.J. Jr. et al. 2006 Depression and thyroid axis function in coronary artery disease: impact of cardiac impairment and gender. Clin Cardiol 29:170−4.
Anxiety S.2.01 Can PTSD be prevented? Strategic interventions in the ‘golden hours’ J. Zohar1 ° . 1 Chaim Sheba Medical Center, Division of Psychiatry, Tel Hashomer, Israel The concept of “golden hours” has recently received attention in medicine. This concept is essentially focused
S112
Symposia
on an immediate intervention right after the trauma (such as cerebular vascular accident (CVA), heart attack, polytrauma, etc), in order to prevent/decrease the impending (usually devastating) sequelae of those events which often trigger a chain of pathological processes. Is there a “golden hour” in psychiatry? Can intervention right after exposure to trauma attenuate the pathological response that we refer to as PTSD or, alternatively, does current practice adhere to “primum non nocere” vis a vis the powerful spontaneous recovery process which characterizes the normal response to trauma? If we conceptualize PTSD as a “failure to recover”, then what we do or don’t do during those “golden hours” might dramatically affect the outcome. How does PTSD develop? Although PTSD is precipitated by trauma exposure, differences in exposure do not fully determine either the development of, or recovery from, PTSD. In recent years interest has grown in identifying biological and clinical risk factors that increase the likelihood that PTSD will develop following trauma exposure. These have ranged from genetic to environmental factors, and have included both pre-existing traits, characteristics of the traumatic event, and aspects of the victim’s peri- and post-traumatic response. Although little is known about predictive factors of PTSD and the immediate response to the trauma, the symptoms which were found to be associated with higher frequency of PTSD include, among others, a significant panic-like response, pronounced distress, dissociative response and past history of anxiety or depression. Those symptoms may reflect the intensity or severity of the current experience, a pre-existing individual trait, or sensitization from prior trauma exposure. The risk factors named above could certainly reflect expressions of either genetic diatheses or early life experiences. For example, early abuse might affect personality and cognitive abilities, but may also be a consequence of these factors. Similarly, factors associated with heritable parental characteristics (e.g., psychopathology) may increase risk for PTSD by increasing exposure to neglect or abuse. Acute distress management: The essence of acute distress management is by helping to contain and attenuate emotional reaction. The goal is to help the traumatized to regain emotional control, to restore interpersonal communications and to encourage returning to full function and activity. At this stage it would be important not to pathologize (talking about fright and not about panic), and to emphasize the importance of returning back to normal routine. The focus is on information, orientation, expectation of returning back to normal and not focusing on the emotional component. Along those lines, group
therapy, which might actually lead to emotional reaction, should be used, if at all, with great caution. It is also recommended at this point of time not to give pharmacological intervention, except in very extreme stress reaction. What effect does the immediate intervention have? It is feasible that intervention (whether psychological or pharmacological) right in the aftermath of exposure to trauma might play a determining role in the evolution of the response to it, increasing or decreasing the development of PTSD. Preclinical and clinical data suggest that amnesia of the traumatic event is associated with a decreased prevalence of PTSD. The clinical data are related, among other things, to follow-up of traumatic brain injury with amnesia and the frequency of PTSD. The preclinical perspective derives from a study of anisomycin (a protein synthesis inhibitor which blocks consolidation) in an animal model of PTSD. Along these lines, psychological defense mechanisms mimicking amnesia (like repression) would be predicted to be useful, whilst psychological intervention enhancing the traumatic memory would be associated with less favourable outcome. Indeed, a single-session debriefing − which often involves reconstruction of the trauma − was associated with a less favourable outcome as compared to non-intervention. This would suggest that pharmacological intervention associated with a decrease in consolidation of the traumatic memory might be beneficial and that interventions associated enriching the traumatic memory would be associated with a worse outcome. Early administration of benzodiaepines (BNZ) was found to be associated with a less favourable outcome in two small studies, and also in an animal model of PTSD. In this study (in preparation), early administration of BNZ (alprazolam) was associated with an increase in PTSD-like behaviour when the rats were exposed a month later to the traumatic cue. This finding might be related to the effect on the HPA axis; BNZ abolishes the cortisol response (which is usually associated with trauma exposure) and therefore might attenuate the natural response − increased cortisol levels − an increase which in itself is associated with a decrease in the fear index. At any rate, the HPA axis is the major constituent of the neuroendocrine response to stress. Clinical studies have suggested that cortisol administration might be associated with a reduced risk of developing PTSD. However, this has not yet been studied properly in PTSD. A recent study by our group, which looked at early administration of different doses of cortisol in an animal model of PTSD demonstrated an effect of post-stressor administration of corticosterone (25 mg/kg) in Sprague-
Symposia Dawley rats on behaviour. These animals showed less PTSD-like behaviour than low-dose or control rats, when measured one month later after a cue reminder was administered. The only medications with a specific indication for PTSD are SSRIs (sertraline and paroxetine). However, they were tested only several months (even years) after the exposure. Would an early administration of SSRIs immediately after the exposure have a preventive effect? The potential role of SSRIs in hippocampal neurogenesis along with clinical observations paved the way to examining this in an animal model of PTSD, showing that early administration of SSRI (sertraline) was associated with a significant decrease in PTSD-like behaviour. Currently, we are studying this in a doubleblind random assignment study with 100 patients in each arm. The results of this study might shed some light on the intriguing question, “Can PTSD be prevented?” These kinds of studies are needed in order to examine what psychological and/or pharmacological interventions should or should not be done during the “golden hours”. Reference(s) [1] Cohen H, Kaplan Z, Matar MA, Loewenthal U, Kozlovsky N, Zohar J, 2006. Anisomycin, a protein synthesis inhibitor, disrupts traumatic memory consolidation and attenuates posttraumatic stress response in rats. Biol Psychiatry, 60(7), 767–776. [2] Matar MA, Cohen H, Kaplan Z, Zohar J, 2006. The effect of early poststressor intervention with sertraline on behavioral responses in an animal model of posttraumatic stress disorder. Neuropsychopharmacology, 31(12), 2610–2618. [3] Cohen H, Matar MA, Buskila D, Kaplan Z, Zohar J. Early post-stressor intervention with high-dose corticosterone attenuates posttraumatic stress response in an animal model of posttraumatic stress disorder. Biological Psychiatry, 64(8), 708–717.
S113
S.2.02 The brain prepared to become anxious: predisposing neurobiology in animals and humans J. Harro1 ° , A. Alttoa1 , L. Herm2 , E. Kiive1 , T. Kurrikoff1 , J. M¨aestu3 , T. M¨allo1 , L. Meren¨akk4 , N. Nordquist5 , L. Oreland5 . 1 University of Tartu, Department of Psychology, Tartu, Estonia; 2 University of Tartu, Department of Chemistry, Tartu, Estonia; 3 University of Tartu, Department of Sport Pedagogics, Tartu, Estonia; 4 University of Tartu, Department of Public Health, Tartu, Estonia; 5 University of Uppsala, Department of Neuroscience Pharmacology, Uppsala, Sweden Individuals experience anxiety with different intensity and frequency, and differ in their proneness to indulge in pathological anxiety. These individual differences obviously are based on neurobiological varieties that remain to be disentangled. The underlying anxiety-prone neurobiology may be genetic, epigenetic, and acquired during different periods of life from early childhood to adulthood. Factors that elicit such neurobiological changes, occurring at different periods of development and life course, interact. In many instances it is likely that preexistent vulnerability factors such as functional polymorphisms in anxiety-related genes would enhance the effects of lifetime impacts. It is also conceivable, however, that early-onset predisposing mechanisms would lead to major developmental changes in the brain that reduce the influence of such impacts that would be anxiety-provoking in other individuals. The agency of the individual should not be ignored either, as persistent levels of anxiety may influence individual behavioural choices that lead to exposition to moderating environments. The serotonin (5-HT) system is the best characterized major neurotransmitter system regarding its role in anxiety, and thus we have examined serotonergic measures in rat models based on preselection of animals with persistently high expression of anxiety. Rats with persistently low activity in the exploration box test (LE-rats) have normal activity levels in a novel home-cage, but high anxiety in the elevated plus-maze as compared to the highexploring (HE-) rats [1]. The density of 5-HT transporters is significantly higher in prefrontal cortex of the LE-rats, and correspondingly the increase in extracellular 5-HT levels in these animals is higher after adding citalopram into perfusion fluid. The LE-rats also have a number of differences in dopaminergic measures, that may contribute to their passive coping strategies. However, while the LE/HE phenotypic distinction is stable over time, and in response to chronic stress LE-rats develop anhedonia more readily, stress attenuates several baseline differences in 5-HT- and dopaminergic systems between LE- and HE-
S.1.05 Depression and general medical condition R. Bunevicius1 ° . 1 Kaunas University of Medicine, Institute of Psychophysiology and Rehabilitation, Palanga, Lithuania Depression often co-exists with physical illnesses, often called as general medical conditions (GMC). Such GMC may precede the depression, may cause it, or may be a consequence of it. Interaction between depression and GMC differs in different persons and different situations and should be evaluated properly. Diagnosing primary depressive disorder it is important to exclude the GMC because it may be responsible for the manifestation of symptoms of depression. A variety of medical conditions can cause depression, including degenerating neurological diseases, such as Alzheimer’s disease; vitamin deficiencies; endocrine diseases, such as thyroid dysfunction or adrenal dysfunction; stroke or tumor of the frontal part of the brain; and certain viral infections, such as mononucleosis. Certain medications, such as steroids or substance abuse, may also cause depression. In all these cases GMC is considered having direct physiological effects causing depressive disorder. Several clinical features suggest a medical origin of mood symptoms including late onset of the initial depressive episode, atypical presentation of mood disorder, treatment resistance or unusual response to treatment. Depressive disorder directly related with GMC is called mood disorder due to GMC in the DSM-IV classification or organic mood (depressive) disorder in the ICD-10 classification. The first step managing organic mood disorder is treatment of the GMC. Successful treatment of the GMC usually results in the resolution of symptoms of depression. This confirms causal role of the GMC for manifestation of depressive disorder. When symptoms of depression remain after cure of the GMC diagnosis of organic mood disorder should be re-evaluated and standard antidepressive treatment should be considered. An example of such an interaction between mood disorder and GMC may be an association between depression and thyroid disorder. It is well recognized that thyroid dysfunction, hypothyroidism and hyperthyroidism, is associated with mood or anxiety disorders. Majority of patients with Graves’ hyperthyroidism have at least one mood or anxiety disorder. Compensation of thyroid dysfunction results in restoration of normal mood in
S111
majority of patients; however, in significant proportion of patients symptoms of anxiety or depression remain even after restoration of euthyroidism [1], suggesting that mental dysfunction may be related with mechanisms, other than thyroid hormone secretion. Thyroid autoimmune process per se may be a mechanism responsible for the manifestation of symptoms of anxiety and/or depression [2]. Another important mechanism connecting GMC and depression is low triiodothyronine (T3) syndrome, reported in serious medical conditions as well as in depression. It was demonstrated by our group [3] that depressed patients with coronary artery disease, especially men, as compared to euthymic patients with coronary artery disease, demonstrate lower T3 concentrations, suggesting that low T3 syndrome may be a causal factor of depression in patients with coronary artery disease. There is no data does compensation of low T3 syndrome result in improvement in symptoms of depression in patients with coronary artery disease or in patients with other GMC. It may be concluded that clinical as well as subclinical, thyroid dysfunction, including patients with low T3 syndrome, or autoimmune involvement of the thyroid axis even with mormal functioning, may be related with mood disorders, including depression. Studies on impact of compensation of subclinical thyroid dysfunction, including low T3 syndrome, on symptoms of depression are needed. Reference(s) [1] Bunevicius R., Prange A.J. Jr. 2006 Psychiatric manifestations of Graves’ hyperthyroidism: pathophysiology and treatment options. CNS Drugs 20:897– 909. [2] Bunevicius R., Peceliuniene J., Mickuviene N. et al. 2007 Mood and thyroid immunity assessed by ultrasonographic imaging in a primary health care. J Affect Disord 97:85−90. [3] Bunevicius R., Varoneckas G., Prange A.J. Jr. et al. 2006 Depression and thyroid axis function in coronary artery disease: impact of cardiac impairment and gender. Clin Cardiol 29:170−4.
Anxiety S.2.01 Can PTSD be prevented? Strategic interventions in the ‘golden hours’ J. Zohar1 ° . 1 Chaim Sheba Medical Center, Division of Psychiatry, Tel Hashomer, Israel The concept of “golden hours” has recently received attention in medicine. This concept is essentially focused
S112
Symposia
on an immediate intervention right after the trauma (such as cerebular vascular accident (CVA), heart attack, polytrauma, etc), in order to prevent/decrease the impending (usually devastating) sequelae of those events which often trigger a chain of pathological processes. Is there a “golden hour” in psychiatry? Can intervention right after exposure to trauma attenuate the pathological response that we refer to as PTSD or, alternatively, does current practice adhere to “primum non nocere” vis a vis the powerful spontaneous recovery process which characterizes the normal response to trauma? If we conceptualize PTSD as a “failure to recover”, then what we do or don’t do during those “golden hours” might dramatically affect the outcome. How does PTSD develop? Although PTSD is precipitated by trauma exposure, differences in exposure do not fully determine either the development of, or recovery from, PTSD. In recent years interest has grown in identifying biological and clinical risk factors that increase the likelihood that PTSD will develop following trauma exposure. These have ranged from genetic to environmental factors, and have included both pre-existing traits, characteristics of the traumatic event, and aspects of the victim’s peri- and post-traumatic response. Although little is known about predictive factors of PTSD and the immediate response to the trauma, the symptoms which were found to be associated with higher frequency of PTSD include, among others, a significant panic-like response, pronounced distress, dissociative response and past history of anxiety or depression. Those symptoms may reflect the intensity or severity of the current experience, a pre-existing individual trait, or sensitization from prior trauma exposure. The risk factors named above could certainly reflect expressions of either genetic diatheses or early life experiences. For example, early abuse might affect personality and cognitive abilities, but may also be a consequence of these factors. Similarly, factors associated with heritable parental characteristics (e.g., psychopathology) may increase risk for PTSD by increasing exposure to neglect or abuse. Acute distress management: The essence of acute distress management is by helping to contain and attenuate emotional reaction. The goal is to help the traumatized to regain emotional control, to restore interpersonal communications and to encourage returning to full function and activity. At this stage it would be important not to pathologize (talking about fright and not about panic), and to emphasize the importance of returning back to normal routine. The focus is on information, orientation, expectation of returning back to normal and not focusing on the emotional component. Along those lines, group
therapy, which might actually lead to emotional reaction, should be used, if at all, with great caution. It is also recommended at this point of time not to give pharmacological intervention, except in very extreme stress reaction. What effect does the immediate intervention have? It is feasible that intervention (whether psychological or pharmacological) right in the aftermath of exposure to trauma might play a determining role in the evolution of the response to it, increasing or decreasing the development of PTSD. Preclinical and clinical data suggest that amnesia of the traumatic event is associated with a decreased prevalence of PTSD. The clinical data are related, among other things, to follow-up of traumatic brain injury with amnesia and the frequency of PTSD. The preclinical perspective derives from a study of anisomycin (a protein synthesis inhibitor which blocks consolidation) in an animal model of PTSD. Along these lines, psychological defense mechanisms mimicking amnesia (like repression) would be predicted to be useful, whilst psychological intervention enhancing the traumatic memory would be associated with less favourable outcome. Indeed, a single-session debriefing − which often involves reconstruction of the trauma − was associated with a less favourable outcome as compared to non-intervention. This would suggest that pharmacological intervention associated with a decrease in consolidation of the traumatic memory might be beneficial and that interventions associated enriching the traumatic memory would be associated with a worse outcome. Early administration of benzodiaepines (BNZ) was found to be associated with a less favourable outcome in two small studies, and also in an animal model of PTSD. In this study (in preparation), early administration of BNZ (alprazolam) was associated with an increase in PTSD-like behaviour when the rats were exposed a month later to the traumatic cue. This finding might be related to the effect on the HPA axis; BNZ abolishes the cortisol response (which is usually associated with trauma exposure) and therefore might attenuate the natural response − increased cortisol levels − an increase which in itself is associated with a decrease in the fear index. At any rate, the HPA axis is the major constituent of the neuroendocrine response to stress. Clinical studies have suggested that cortisol administration might be associated with a reduced risk of developing PTSD. However, this has not yet been studied properly in PTSD. A recent study by our group, which looked at early administration of different doses of cortisol in an animal model of PTSD demonstrated an effect of post-stressor administration of corticosterone (25 mg/kg) in Sprague-
Symposia Dawley rats on behaviour. These animals showed less PTSD-like behaviour than low-dose or control rats, when measured one month later after a cue reminder was administered. The only medications with a specific indication for PTSD are SSRIs (sertraline and paroxetine). However, they were tested only several months (even years) after the exposure. Would an early administration of SSRIs immediately after the exposure have a preventive effect? The potential role of SSRIs in hippocampal neurogenesis along with clinical observations paved the way to examining this in an animal model of PTSD, showing that early administration of SSRI (sertraline) was associated with a significant decrease in PTSD-like behaviour. Currently, we are studying this in a doubleblind random assignment study with 100 patients in each arm. The results of this study might shed some light on the intriguing question, “Can PTSD be prevented?” These kinds of studies are needed in order to examine what psychological and/or pharmacological interventions should or should not be done during the “golden hours”. Reference(s) [1] Cohen H, Kaplan Z, Matar MA, Loewenthal U, Kozlovsky N, Zohar J, 2006. Anisomycin, a protein synthesis inhibitor, disrupts traumatic memory consolidation and attenuates posttraumatic stress response in rats. Biol Psychiatry, 60(7), 767–776. [2] Matar MA, Cohen H, Kaplan Z, Zohar J, 2006. The effect of early poststressor intervention with sertraline on behavioral responses in an animal model of posttraumatic stress disorder. Neuropsychopharmacology, 31(12), 2610–2618. [3] Cohen H, Matar MA, Buskila D, Kaplan Z, Zohar J. Early post-stressor intervention with high-dose corticosterone attenuates posttraumatic stress response in an animal model of posttraumatic stress disorder. Biological Psychiatry, 64(8), 708–717.
S113
S.2.02 The brain prepared to become anxious: predisposing neurobiology in animals and humans J. Harro1 ° , A. Alttoa1 , L. Herm2 , E. Kiive1 , T. Kurrikoff1 , J. M¨aestu3 , T. M¨allo1 , L. Meren¨akk4 , N. Nordquist5 , L. Oreland5 . 1 University of Tartu, Department of Psychology, Tartu, Estonia; 2 University of Tartu, Department of Chemistry, Tartu, Estonia; 3 University of Tartu, Department of Sport Pedagogics, Tartu, Estonia; 4 University of Tartu, Department of Public Health, Tartu, Estonia; 5 University of Uppsala, Department of Neuroscience Pharmacology, Uppsala, Sweden Individuals experience anxiety with different intensity and frequency, and differ in their proneness to indulge in pathological anxiety. These individual differences obviously are based on neurobiological varieties that remain to be disentangled. The underlying anxiety-prone neurobiology may be genetic, epigenetic, and acquired during different periods of life from early childhood to adulthood. Factors that elicit such neurobiological changes, occurring at different periods of development and life course, interact. In many instances it is likely that preexistent vulnerability factors such as functional polymorphisms in anxiety-related genes would enhance the effects of lifetime impacts. It is also conceivable, however, that early-onset predisposing mechanisms would lead to major developmental changes in the brain that reduce the influence of such impacts that would be anxiety-provoking in other individuals. The agency of the individual should not be ignored either, as persistent levels of anxiety may influence individual behavioural choices that lead to exposition to moderating environments. The serotonin (5-HT) system is the best characterized major neurotransmitter system regarding its role in anxiety, and thus we have examined serotonergic measures in rat models based on preselection of animals with persistently high expression of anxiety. Rats with persistently low activity in the exploration box test (LE-rats) have normal activity levels in a novel home-cage, but high anxiety in the elevated plus-maze as compared to the highexploring (HE-) rats [1]. The density of 5-HT transporters is significantly higher in prefrontal cortex of the LE-rats, and correspondingly the increase in extracellular 5-HT levels in these animals is higher after adding citalopram into perfusion fluid. The LE-rats also have a number of differences in dopaminergic measures, that may contribute to their passive coping strategies. However, while the LE/HE phenotypic distinction is stable over time, and in response to chronic stress LE-rats develop anhedonia more readily, stress attenuates several baseline differences in 5-HT- and dopaminergic systems between LE- and HE-