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ECT: Relationships among therapeutic outcome, amnesia, and EEG response
21
S-6 Molecular Biology ofSerotonergic System and Aggressive Behaviours findings with oxytocin-related peptides). ECT has been shown to improve glucose control in diabetic humans and animals and our studies revealed that this may be a consequence of its ability to immediately raise plasma insulin levels through an as yet unknown mechanism. The effects of ECT on plasma catecholeamines has been little studied but they are thought to be elevated at least initially in treatment, perhaps contributing to the elevations in blood pressure that occur during the seizure. We have developed the new technique of continuous bp monitoring using finger cuff plethysmography (Finapres, Ohmeda) to explore in detail the changes that occur during ECT. These data unexpectedly reveal that an increase in bp is not an invariable consequence of a seizure; in some cases bp actually falls. The relation to sympatholytic activation and plasma NA release is being explored. [I] Smith et al (1994) Psychological Medicine 24: 547-555. [2] Williams et al (1992) British Journal of Psychiatry 161: 94-98.
I8-5-41
Medication Resistance, ECTResponse and Relapse Prevention
H.A. Sackeim, 1. Prudic, R.E Haskett, B. Mulsant, H. Pettinati. New York State Psychiatric Institute, Western Psychiatric Institute and Clinic, Carrier Foundation, USA The most indication for the use of electroconvulsive therapy (EC) in major depression is the failure to respond to adequate trials of antidepressant medications. The most common treatment to prevent relapse following response to ECT is pharmacotherapy with antidepressants. Were it the case that the likelihood of achieving a short-term response with ECT was independent of previous medication history, this would suggest that the mechanisms of action of ECT and antidepressants were independent. There would also be important theoretical implications were it the case that continuation/maintenance treatment with antidepressants was effective in relapse prevention, when the same medications proved ineffective in treatment of the acute episode. This would suggest either that (a) the neuro-biological changes needed to prevent relapse are different in degree or kind than those needed to achieve remission of the episode, or (b) ECT changes the neurobiological substrate so that a medication can exert an action that it could not achieve during acute phase treatment. However, regardless of the theoretical implications, these issues are of paramount clinical concern. We need to know (I) whether medication resistance impacts on response to ECT and (2) how best to treat patients pharmacologically following response to ECT. New data on both of these issues will be presented from an ongoing multi-center trial. Further, ECT is the only biological treatment in psychiatry that is typically discontinued once it is shown to be effective. The efficacy of continuation/maintenance ECT and methods to optimize this form of treatment for relapse prevention will be discussed.
I8-5-51
ECT: Relationships among Therapeutic Outcome, Amnesia, and EEG Response
R.D. Weiner, A.D. Krystal, C.E. Coffey. Department ofPsychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA Electroconvulsive therapy (ECT) has long been known to be associated with EEG effects of various types. However, the relationships between such changes and both therapeutic outcome and cognitive side effects have been unclear. The present investigation attempts to characterize these relationships using data from three separate studies that include quantitative EEG assessment both prior to and shortly following an ECT course in patients treated for major depression. Analyses also include a determination of the extent to which the pre-ECT EEG can predict outcome measures. EEG indices utilized include spectral amplitude and coherence. Findings suggest that relationships between EEG indices and measures of treatment outcome exist and that such relationships may be useful for an understanding of neurobiological mechanisms of action.
I
s-61
1
8-6-1
Molecular Biology of Serotonergic System and Aggressive Behaviours 1
Preclinical Models of Aggressive Behavior: The Role of Serotonin
B. Eichelman. Department of Psychiatry, Temple University School of Medicine, Philadelphia, Pennsylvania, United States Serotonin is linked to aggressive behavior within many preclinical, animal model systems evaluating agonistic or aggressive behavior. Predatory and affective categories appear similarly altered by serotonergic modulation. In general, reduction in the activity of central serotonergic systems is associated with increases in aggressive behavior, while facilitation of the serotonergic system may be associated with decrements in "pathological aggression" and with an enhancement in affiliative behaviors. Environmental studies using isolation have demonstrated that isolated mice develop reduced serotonin turnover and enhanced aggressive behavior. Genetic studies have shown that rodents and small mammals bred for aggressive and pacific behaviors differ in terms of regional brain levels of serotonin. Biochemically, reductions in the levels of brain serotonin through pharmacologic treatment, dietary restriction, and lesions all enhance animal models of aggressive behavior. Pharmacologically, general enhancement of the serotonin system with tryptophan loading can reduce "pathological aggressive behavior". More specifically, stimulation of the serotonin 5HT I system with "serenics" is effective in reducing affective aggression in animal models. Recently, "knock out" technology has generated mice deficient in the 5HT 1B receptor. These demonstrate enhanced isolation-induced aggression. In primate (ethological) models, a similar naturally occurring association between low csf 5HIAA levels and aggression and "risk-taking" has also been found with a converse association of enhanced affiliative behaviors and higher levels of csf 5HIAA. Continued utilization of such animal models may elucidate the role of various serotonin receptor systems in modulating aggressive behavior and may also illuminate the association of 5HT with other neuromodulators which alter aggressive behaviors.
I 8-6-21 Individual Differences in 5-HT1A Receptors and Aggressive Behavior in Monkeys M. Raleigh, D. Nielsen, D. Goldman, M. Linnoila, M. McGuire. Dept. of Psychiatry, UCLA, Los Angeles and NIAAA, Bethesda. USA. Individual differences in indices of serotonergic function have been linked to persistent individual differences in aggression, alcohol abuse, and alcohol-induced aggression. As part of our efforts to develop a nonhuman primate model of the behavioral consequences of serotonergic dysfunction, we examined the relationship between genetically determined differences in the 5-HT I A receptor and these three behavioral patterns in vervet monkeys. Purified DNA was obtained from 28 adult monkeys that had been born and raised in species typical social groups. Two polymorphisms were identified. Relative to both population means and to the 23 other animals that had undergone genetic analysis, the five individuals that were homozygous for the least common form of the allele manifested significantly lower concentrations of cerebrospinal fluid 5-HIAA (247 ± 42 pmollml vs. 401 ± 51 pmollml) but not of HVA. In normal, non-stressful settings these five subjects were 8.2 times as likely to initiate and prolong intense, injurious aggression than were control subjects. When given a choice between alcohol (7.5% v/v) or vehicle, each of the five subjects consistently consumed more alcohol than control subjects. During the four hours after presentation of alcohol, the five subjects were 17.6 times as likely to initiate injurious aggression as were control animals. These observations suggest that some of the behavioral pathologies associated with diminished serotonergic function may be more specifical1ylinked to alterations in 5-HTIA receptors. Supported in part by the Dana Foundation, the Veterans Administration, and the Giles and Elsie Mead Foundation.
S-6 Molecular Biology ofSerotonergic System and Aggressive Behaviours findings with oxytocin-related peptides). ECT has been shown to improve glucose control in diabetic humans and animals and our studies revealed that this may be a consequence of its ability to immediately raise plasma insulin levels through an as yet unknown mechanism. The effects of ECT on plasma catecholeamines has been little studied but they are thought to be elevated at least initially in treatment, perhaps contributing to the elevations in blood pressure that occur during the seizure. We have developed the new technique of continuous bp monitoring using finger cuff plethysmography (Finapres, Ohmeda) to explore in detail the changes that occur during ECT. These data unexpectedly reveal that an increase in bp is not an invariable consequence of a seizure; in some cases bp actually falls. The relation to sympatholytic activation and plasma NA release is being explored. [I] Smith et al (1994) Psychological Medicine 24: 547-555. [2] Williams et al (1992) British Journal of Psychiatry 161: 94-98.
I8-5-41
Medication Resistance, ECTResponse and Relapse Prevention
H.A. Sackeim, 1. Prudic, R.E Haskett, B. Mulsant, H. Pettinati. New York State Psychiatric Institute, Western Psychiatric Institute and Clinic, Carrier Foundation, USA The most indication for the use of electroconvulsive therapy (EC) in major depression is the failure to respond to adequate trials of antidepressant medications. The most common treatment to prevent relapse following response to ECT is pharmacotherapy with antidepressants. Were it the case that the likelihood of achieving a short-term response with ECT was independent of previous medication history, this would suggest that the mechanisms of action of ECT and antidepressants were independent. There would also be important theoretical implications were it the case that continuation/maintenance treatment with antidepressants was effective in relapse prevention, when the same medications proved ineffective in treatment of the acute episode. This would suggest either that (a) the neuro-biological changes needed to prevent relapse are different in degree or kind than those needed to achieve remission of the episode, or (b) ECT changes the neurobiological substrate so that a medication can exert an action that it could not achieve during acute phase treatment. However, regardless of the theoretical implications, these issues are of paramount clinical concern. We need to know (I) whether medication resistance impacts on response to ECT and (2) how best to treat patients pharmacologically following response to ECT. New data on both of these issues will be presented from an ongoing multi-center trial. Further, ECT is the only biological treatment in psychiatry that is typically discontinued once it is shown to be effective. The efficacy of continuation/maintenance ECT and methods to optimize this form of treatment for relapse prevention will be discussed.
I8-5-51
ECT: Relationships among Therapeutic Outcome, Amnesia, and EEG Response
R.D. Weiner, A.D. Krystal, C.E. Coffey. Department ofPsychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA Electroconvulsive therapy (ECT) has long been known to be associated with EEG effects of various types. However, the relationships between such changes and both therapeutic outcome and cognitive side effects have been unclear. The present investigation attempts to characterize these relationships using data from three separate studies that include quantitative EEG assessment both prior to and shortly following an ECT course in patients treated for major depression. Analyses also include a determination of the extent to which the pre-ECT EEG can predict outcome measures. EEG indices utilized include spectral amplitude and coherence. Findings suggest that relationships between EEG indices and measures of treatment outcome exist and that such relationships may be useful for an understanding of neurobiological mechanisms of action.
I
s-61
1
8-6-1
Molecular Biology of Serotonergic System and Aggressive Behaviours 1
Preclinical Models of Aggressive Behavior: The Role of Serotonin
B. Eichelman. Department of Psychiatry, Temple University School of Medicine, Philadelphia, Pennsylvania, United States Serotonin is linked to aggressive behavior within many preclinical, animal model systems evaluating agonistic or aggressive behavior. Predatory and affective categories appear similarly altered by serotonergic modulation. In general, reduction in the activity of central serotonergic systems is associated with increases in aggressive behavior, while facilitation of the serotonergic system may be associated with decrements in "pathological aggression" and with an enhancement in affiliative behaviors. Environmental studies using isolation have demonstrated that isolated mice develop reduced serotonin turnover and enhanced aggressive behavior. Genetic studies have shown that rodents and small mammals bred for aggressive and pacific behaviors differ in terms of regional brain levels of serotonin. Biochemically, reductions in the levels of brain serotonin through pharmacologic treatment, dietary restriction, and lesions all enhance animal models of aggressive behavior. Pharmacologically, general enhancement of the serotonin system with tryptophan loading can reduce "pathological aggressive behavior". More specifically, stimulation of the serotonin 5HT I system with "serenics" is effective in reducing affective aggression in animal models. Recently, "knock out" technology has generated mice deficient in the 5HT 1B receptor. These demonstrate enhanced isolation-induced aggression. In primate (ethological) models, a similar naturally occurring association between low csf 5HIAA levels and aggression and "risk-taking" has also been found with a converse association of enhanced affiliative behaviors and higher levels of csf 5HIAA. Continued utilization of such animal models may elucidate the role of various serotonin receptor systems in modulating aggressive behavior and may also illuminate the association of 5HT with other neuromodulators which alter aggressive behaviors.
I 8-6-21 Individual Differences in 5-HT1A Receptors and Aggressive Behavior in Monkeys M. Raleigh, D. Nielsen, D. Goldman, M. Linnoila, M. McGuire. Dept. of Psychiatry, UCLA, Los Angeles and NIAAA, Bethesda. USA. Individual differences in indices of serotonergic function have been linked to persistent individual differences in aggression, alcohol abuse, and alcohol-induced aggression. As part of our efforts to develop a nonhuman primate model of the behavioral consequences of serotonergic dysfunction, we examined the relationship between genetically determined differences in the 5-HT I A receptor and these three behavioral patterns in vervet monkeys. Purified DNA was obtained from 28 adult monkeys that had been born and raised in species typical social groups. Two polymorphisms were identified. Relative to both population means and to the 23 other animals that had undergone genetic analysis, the five individuals that were homozygous for the least common form of the allele manifested significantly lower concentrations of cerebrospinal fluid 5-HIAA (247 ± 42 pmollml vs. 401 ± 51 pmollml) but not of HVA. In normal, non-stressful settings these five subjects were 8.2 times as likely to initiate and prolong intense, injurious aggression than were control subjects. When given a choice between alcohol (7.5% v/v) or vehicle, each of the five subjects consistently consumed more alcohol than control subjects. During the four hours after presentation of alcohol, the five subjects were 17.6 times as likely to initiate injurious aggression as were control animals. These observations suggest that some of the behavioral pathologies associated with diminished serotonergic function may be more specifical1ylinked to alterations in 5-HTIA receptors. Supported in part by the Dana Foundation, the Veterans Administration, and the Giles and Elsie Mead Foundation.