- Email: [email protected]
Disorder of synaptic homeostasis in depression and its treatment
X0X Gene expression in the serotonergic
control of neuronal plasticity and its implication in psychiat?
The 5-H’ft~ receptor plays a key role in homeostatic regulation of the serotonergic activity. Mice without a functional 5‘HTIA receptor have normal levels of serotonin and serotonin turnover. However, the inhibitory effect of ~-HT~A agonist 8-OH-DPAT on serotonin release is absent. Because of the known involvement of serotonin in the modulation of anxiety-related behavior, we investigated the behavior of the knockout mice in two animal models of anxiety test: the open field and the elevated plus maze. A factor analysis grouped our behavioral measures from the open field into two independent categories: an exploratory-like factor (total distance traveled, rearing, and nose poking), and an anxiety-like factor (time spent in the center and relative distance traveled in the center). The knockout mice displayed decreased exploratory activity and increased anxiety. Behavioral measures in the elevated plus maze also fall into an anxiety-like factor (time spent, numbers of entries, and head-dips in the open arms) and an exploratory/activity factor (total entries, entries in the closed arms, rearings). The knockout mice again displayed increased anxiety. Heterozygous mice express intermediate levels of the 5-HTm receptor as well as intermediate phenotypes. These results demonstrate that the functional state of the serotonin system resulting from deletion of the S-HTIA receptor renders the animal with heightened anxiety and decreased exploratory behavior. Future research will characterize in detail the functional state of the serotonin system in these mice. We will also test whether anxiolytic drugs can readjust the functional state of this system and improve the animals’ performance in anxiety test. The 5-HTlB receptor plays an important role in regulating serotonin release from terminals and in modulating dopaminergic activity. Mice without a functional 5-HTlB receptor have heightened responses to dopamine reuptake inhibitors. Since the dopamine system plays a key role in rewarding and drugs of abuse, we studied changes in vulnerability to cocaine in these mice using the cocaine self-administration paradigm. A progressive-ratio schedule was used in which the number of lever presses required to deliver an injection of cocaine was increased until the mice no longer responded (break point). For all doses of cocaine tested (0.54.0 mg/kg per injection; i.v.), knockout mice had higher break points than wild type mice. The specificity of cocaine’s effect was conlirmed with food as reinforcement in a same schedule in which knockout and wild type mice showed no difference. The knockout mice also showed heightened locomotor response to acute cocaine which is characteristic of mice that have sensitized to cocaine. A biochemical marker for cocaine sensitization, AFosB, also has high baseline expression in the striatum of the knockout mice. Other behavioral changes in the 5-HTlB knockout mice include increased alcohol intake and increased aggression. It is possible that increased impulsivity in the 5-HTlB knockout mice is the deficit responsible for both increased aggression and vulnerability to drugs of abuse. The gene encoding the 5-HT5A receptor has been isolated in rodents and humans. However, there has been no evidence that the receptor protein was expressed, and the function of this receptor has remained unknown. Comparative autoradiography studies of brains of wild type and 5-HT5A knockout mice revealed the existence of 5-HTSA-specific binding sites in the olfactory bulb, neocortex and medial habenma. When exposed to novel environments, the knockout mice displayed increased exploratory activity (increased locomotion, rearing, nose-poking, and novel object exploration in the open field), even though their activity level is the same as the wild type mice in a familiar environment. When anxiety-related behaviors were tested (open field, elevated plus maze, and bearing behavior), there were no difference between the knockout mice and wild type mice. These results suggest that exploratory behavior may be an independent dimension of behavior rather than a mere absence of anxiety, and that deletion of the 5-HT5A receptor may have altered the neural circuits involved in exploratory behavior but not in baseline activity or anxiety. To conclude, the 5-HT receptor knockout mice not only provide a tool to study the function of these receptors, they also serve as animal models with altered functional state of the serotonin system and with vulnerability to certain psychiatric disorders.
-1
s75
Disorder of synaptic homeostasis in depression and its treatment
D.G. &shame-Smith, T.S.C. Zetterstrom, Q. Pei. Oxford Uniuer,sit?/SmithKline Beecham Centre for Applied Neuropsychobiology, University Department of Clinical Pharmacology, Oxford. UK Depression is a complex disorder: slow moving, programmed into the biology of the individual, often dependent on a genetic background, and often triggered by stress. There is a chronology to it. with mainly adult age of onset, an episodic natural history, sometimes a seasonality, a diurnality, and an abnormal chronobiology. Antidepressant treatments are developed on the basis of an acute pharmacology, generally involving changes in noradrenaline and/or 5HT function. However, antidepressant drugs take 24 weeks to produce a clear therapeutic effect. ECT twice weekly requires 3-4 treatments before a therapeutic response is seen and antidepressant drugs are continued subsequently to prevent relapse. These phenomena suggest something more than an acute simple and transient point-to-point pharmacological effect of the treatments. The delay in onset of the therapeutic effect is mirrored by preclinical and clinical data that show chronic neuroadaptive pharmacological responses to antidepressant drugs, ECT (electroconvulsive shock: ECS in animals), and lithium (Grahame-Smith, 1997). Although changes occur in the number of many neurotransmitter receptor binding sites and signalling cascades during chronic antidepressant drug treatment, ECS, and lithium treatment in experimental animals, so far these changes have not provided a coherent explanation for the functional changes observed. It is the search for a coherent explanation that has prompted the formulation of the following hypothesis, (Grahame-Smith 1997). Mood depends on the numerical, structural, and functional homeostasis of sets of indeterminate synapses. This synaptic homeostasis depends on the normal physiological functioning of a neurotrophic system involving the monoamines, particularly 5-HT but perhaps also noradrenaline, which may act, along with other factors, to release neurotrophic factors such as BDNF. 5-HT can have important short term effects through biochemical cascades, altering post-translational factors to maintain immediate synaptic function, but it also has longer term synaptotrophic and neurotrophic effects, involving concerted and coherent changes in gene expression. The neurotrophic factors are also involved in enabling longer term neurotrophic effects through gene expression promoting synaptic cohesion and tine neuronal integrity. This homeostatic system is linely balanced and vulnerable to dysfunction. First, it must be able to react to external mental and physical stresses so as to maintain normality of function in those synapses involved in mood control. A genetically determined vulnerability would involve an inability to mount the neurobiological defence against stress (a neuroadaptive reponse), which normally allows psychological coping. Antidepressant treatment will act to enable the brain prone to a dysfunction of synaptic homeostasis to mount an adequate synaptotrophic and neurotrophic response, whether this be through the monoamine systems, as with the current antidepressant drugs, or through excitatory neurotransmitter systems secondarily affecting monoamine and/or neurotrophic factor function as seems likely with ECT. It is suggested that lithium, whatever its point-to-point molecular target, promotes the neurotrophic effects of 5-HT, reduces the vulnerabilty to synaptic (homeostatic) dysfunction, and thereby acts as a prophylactic in affective disorder. In order to investigate this hypothesis we have studied the expression of certain genes that might be involved in the neuroadaptive responses to the actions of antidepressant drugs, ECS, and lithium in rats, using protocols previously shown to affect 5-HT behavioural functions, In addition, we have manipulated brain 5-HT function with precursor treatment, agonists and antagonists. Others have similarly used these approaches in rats and mice to study neuroadaptive responses (see Duman et al, 1997 and Grahame-Smith, 1997 for full references). It has previously been shown that various antidepressant treatments alter the expression of some early immediate genes, and that 5-HT plays
S76
S.09 Treatment of the comorbidity
a role in these effects. Thus para-chloroamphetamine, which releases 5-HT, the 5-HT2* agonist DOI, and increases in extracellular brain 5HT concentrations all increase c-fos imrnunocytochemical expression in several brain areas. Several antidepressant drugs administered chronically, but not acutely, increase BDNF and TRKb mRNA in the hippocampus and block the down-regulation of BDNF mRNA in the hippocampus produced by restraint stress (Duman et el., 1997). Repeated ECS given in a way that enhances 5-HT behavioural functions causes a prolonged upregulation of BDNF mRNA in hippocampus and piriform cortex (ZetterstrGm et al 1998). Increasing brain 5-HT concentrations acutely increases BDNF gene expression in the frontal cortex but inhibits it in the dentate gyrus. ECS also causes an upregulation of mRNA expression of G-protein coupled potassium-channel subunits in the denture gyrus, an upregulation of the expression of certain potassium channel genes whose corresponding proteins are exclusively located on the dendrites of the granule cells, and increases the expression of the MAP2 mRNA in the dentate gyms (Pei et al., 1997 and 1998). MAP2 protein is more or less restricted to dendrites and these findings suggest that new dendritic elements may be formed during these treatments. Elevation of extracellular brain 5-HT concentrations by MAO inhibition and L-tryptophan administration stimulates mRNA expression of an additional dendritically localised gene ARC (active regulated cytoskeletal associated protein) in the cortex and the striatum and this effect is attenuated by ketanserin, a 5-HT2* antagonist. Evidence is therefore accumulating to suggest that antidepressant drugs and electroconvulsive shock (vis-B-vis ECT) might be acting acutely via neurotransmitter function, i.e. antidepressant drugs via noradrenaline and/or 5-HT, and ECT probably via excitatory neurotransmitters such as glutamate, to set in train neurotrophic and synaptotrophic processes that result in the formation or strengthening of synapses and neuronal networks necessary for the maintenance of normal mood. References 111 Duman. R. S.. G. R. Henineer and E. J. Nestler. 1997. A molecular and cellular theory bf dep&ion. Archives of General Psychiatry, 54 (7), 597606. [2] Graham&Smith, D. G., 1998. Chapter 7: Disorder of synaptic homeostasis as a canae of depression and a target for treabnent. In: M. Briley and S. Montgomery, eds. Antidepressant therapy at the dawn of the third millennium. London: Martin Duniti. [3] Pei, Q., P. I. W. Bnmet and T. S. C. Zetterstriim, 1998. Changes in mRNA abundance of micro tubular-associated proteins in the rat brain following electroconvulsive shock. Neuroreport, 9 (3), 39 l-394. [4] Pei, Q., et al., 1997. Differential effects of acute and chronic electroconvulsive shock on the abundance of messenger RNAs for voltage-dependent potassium channel subunits in the rat brain. Neuroscience, 78 (2), 343-350. [S] ZetterstrGm, T. S. C., Q. Pei and D. G. Grahame-Smith, 1998. Repeated electroconwlsive shock extends the duration of gene expression for BDNG’s rat brain compared with a single administration. Brain Research. Molecular Brain Research (In Press).
S.09 Treatment of the comorbidity and depressive states
Is.09.011 Do anxious
and depressive genetic factors?
of anxious
states share common
C.A. Prescott, KS. Kendler. Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatv, Virginia Commonwealth University, Richmond, Virginia, USA Clinical observation and prior research support a strong association between depressive and anxiety disorders. Family studies showing increased risk of anxiety disorders among the relatives of probands with is in major depression, and vice versalm3, suggest this co-occurrence part due to common etiological factors which are transmitted within families. Our research group previously reported on the comorbidity of major depression (MD) and generalized anxiety (GA) in a sample of 1,030 female twin pairs from the Commonwealth of Virginia, USA4. The two disorders were found to share the same genetic factors, and
of anxiousand
depressive states
these accounted for about 3&40% of the variation in liability for these disorders. The remaining variation in risk was due to individual-specific environmental factors. Half of this environmental variation was shared between MD and GA, and the remainder was disorder-specific. In 1993, we began a new, population-based longitudinal study of malemale and male-female twin pairs. In this paper we present preliminary results from an attempt to replicate in male twins our earlier findings on the etiology of the comorbidity of MD and GA in women. Method: Subjects are Caucasian adult male twins, born between 1940 and 1974, ascertained through the population-based Virginia T!vin Registry, and participating in a longitudinal study of common psychiatric and substance use disorders. Data for the current analyses were obtained in an ongoing second wave of interviews, scheduled to be completed in mid-1998. As of April 1998, data were available for analysis on about 50% of the anticipated final sample, including 375 identical (monozygotic or MZ) and 233 fraternal (dizygotic or DZ) twin pairs. Zygosity determinations were based on an algorithm of the twin’s responses to questionnaire items. The algorithm was validated by analysis of 15 highly informative DNA polymorphisms on a random sample of 174 twin pairs, and was found to correctly classify 94% of twin pairs. Diagnostic assessments were conducted using structured psychiatric interviews based on the Structured Clinical Interview for DSM-III-R (SCID’) but adapted to obtain information for both DSM-Ill-R and DSM-IV diagnoses. In-person interviews were conducted by interviewers who were blind to clinical information about the cotwin. Interviewers had a master’s degree in a mental-health related discipline or a bachelor’s degrees with at least 2 years relevant experience. The current analyses are based on DSM-IV defined MD. Because of concerns about low prevalences of GA, we use a less stringent definition of GA, requiring a 1-month duration and not requiring the anxiety be pervasive. Our analyses assume a liability/threshold model, in which there is a continuous, normally distributed, underlying liability of developing a disorder, and individuals who exceed a threshold manifest the disorder, while those below the threshold do not. The twin model includes three sources of population variation in liability: additive genetic effects (A); family or “common” environment (C); and individual-specific environment and measurement error(E). The estimates for the three components derive from comparisons of the similarity of monozygotic (MZ) and dizygotic (DZ) twin pairs within and across diagnoses. MZ and DZ pairs are assumed to have equally similar family environments, but different degrees of genetic similarity, with MZ pairs being perfectly correlated, but DZ pairs correlated .5 on average. Thus, if the two types of twin pairs are equally similar in their resemblance for a characteristic, common environmental factors are inferred to be operating. To the degree that MZ twin pairs are more similar than DZ pairs, we can infer the etiological influence of genetic factors. Results: Lifetime prevalences were 29% for MD and 12% for GA. The pair correlations for MD and GA were modest, but for both disorders, MZ twin pair resemblance exceeds that among DZ pairs for both MD (rMz = .22, rDz = .16) And GA (rm = .25, r~z = .16), although the differences were not statistically significant. The lifetime co-occurrence of MD and GA in this sample was substantial. Among men with a history of GA, nearly three-quarters had experienced an episode of MD. The correlation in shared liability for these disorders was estimated as .6l. To estimate the sources of this overlapping liability, bivariate twin models use MZ-DZ differences in the cross-twin cross-disorder correlations. Among MZ pairs, MD in one twin was correlated .34 with GA in the cotwin. This value actually exceeds the cross-twin within-disorder correlations for both disorders, suggesting that the cotwin of an MZ twin with a history of MD is equally likely to develop GA or MD. In contrast, among DZ pairs, MD in one twin was correlated near zero with GA in the cotwin. Taken together, these data suggest that the overlapping liability is due in part to genetic but not common environmental sources. Formal bivariate twin models applied to these data supported this suggestion. The best fitting model was one which modeled all the genetic sources of variation in MD and GA as shared by the two disorders. The remaining variation was estimated as due to individual-specific factors, about half of which was shared by the two disorders, and the remainder was disorder-specific.
control of neuronal plasticity and its implication in psychiat?
The 5-H’ft~ receptor plays a key role in homeostatic regulation of the serotonergic activity. Mice without a functional 5‘HTIA receptor have normal levels of serotonin and serotonin turnover. However, the inhibitory effect of ~-HT~A agonist 8-OH-DPAT on serotonin release is absent. Because of the known involvement of serotonin in the modulation of anxiety-related behavior, we investigated the behavior of the knockout mice in two animal models of anxiety test: the open field and the elevated plus maze. A factor analysis grouped our behavioral measures from the open field into two independent categories: an exploratory-like factor (total distance traveled, rearing, and nose poking), and an anxiety-like factor (time spent in the center and relative distance traveled in the center). The knockout mice displayed decreased exploratory activity and increased anxiety. Behavioral measures in the elevated plus maze also fall into an anxiety-like factor (time spent, numbers of entries, and head-dips in the open arms) and an exploratory/activity factor (total entries, entries in the closed arms, rearings). The knockout mice again displayed increased anxiety. Heterozygous mice express intermediate levels of the 5-HTm receptor as well as intermediate phenotypes. These results demonstrate that the functional state of the serotonin system resulting from deletion of the S-HTIA receptor renders the animal with heightened anxiety and decreased exploratory behavior. Future research will characterize in detail the functional state of the serotonin system in these mice. We will also test whether anxiolytic drugs can readjust the functional state of this system and improve the animals’ performance in anxiety test. The 5-HTlB receptor plays an important role in regulating serotonin release from terminals and in modulating dopaminergic activity. Mice without a functional 5-HTlB receptor have heightened responses to dopamine reuptake inhibitors. Since the dopamine system plays a key role in rewarding and drugs of abuse, we studied changes in vulnerability to cocaine in these mice using the cocaine self-administration paradigm. A progressive-ratio schedule was used in which the number of lever presses required to deliver an injection of cocaine was increased until the mice no longer responded (break point). For all doses of cocaine tested (0.54.0 mg/kg per injection; i.v.), knockout mice had higher break points than wild type mice. The specificity of cocaine’s effect was conlirmed with food as reinforcement in a same schedule in which knockout and wild type mice showed no difference. The knockout mice also showed heightened locomotor response to acute cocaine which is characteristic of mice that have sensitized to cocaine. A biochemical marker for cocaine sensitization, AFosB, also has high baseline expression in the striatum of the knockout mice. Other behavioral changes in the 5-HTlB knockout mice include increased alcohol intake and increased aggression. It is possible that increased impulsivity in the 5-HTlB knockout mice is the deficit responsible for both increased aggression and vulnerability to drugs of abuse. The gene encoding the 5-HT5A receptor has been isolated in rodents and humans. However, there has been no evidence that the receptor protein was expressed, and the function of this receptor has remained unknown. Comparative autoradiography studies of brains of wild type and 5-HT5A knockout mice revealed the existence of 5-HTSA-specific binding sites in the olfactory bulb, neocortex and medial habenma. When exposed to novel environments, the knockout mice displayed increased exploratory activity (increased locomotion, rearing, nose-poking, and novel object exploration in the open field), even though their activity level is the same as the wild type mice in a familiar environment. When anxiety-related behaviors were tested (open field, elevated plus maze, and bearing behavior), there were no difference between the knockout mice and wild type mice. These results suggest that exploratory behavior may be an independent dimension of behavior rather than a mere absence of anxiety, and that deletion of the 5-HT5A receptor may have altered the neural circuits involved in exploratory behavior but not in baseline activity or anxiety. To conclude, the 5-HT receptor knockout mice not only provide a tool to study the function of these receptors, they also serve as animal models with altered functional state of the serotonin system and with vulnerability to certain psychiatric disorders.
-1
s75
Disorder of synaptic homeostasis in depression and its treatment
D.G. &shame-Smith, T.S.C. Zetterstrom, Q. Pei. Oxford Uniuer,sit?/SmithKline Beecham Centre for Applied Neuropsychobiology, University Department of Clinical Pharmacology, Oxford. UK Depression is a complex disorder: slow moving, programmed into the biology of the individual, often dependent on a genetic background, and often triggered by stress. There is a chronology to it. with mainly adult age of onset, an episodic natural history, sometimes a seasonality, a diurnality, and an abnormal chronobiology. Antidepressant treatments are developed on the basis of an acute pharmacology, generally involving changes in noradrenaline and/or 5HT function. However, antidepressant drugs take 24 weeks to produce a clear therapeutic effect. ECT twice weekly requires 3-4 treatments before a therapeutic response is seen and antidepressant drugs are continued subsequently to prevent relapse. These phenomena suggest something more than an acute simple and transient point-to-point pharmacological effect of the treatments. The delay in onset of the therapeutic effect is mirrored by preclinical and clinical data that show chronic neuroadaptive pharmacological responses to antidepressant drugs, ECT (electroconvulsive shock: ECS in animals), and lithium (Grahame-Smith, 1997). Although changes occur in the number of many neurotransmitter receptor binding sites and signalling cascades during chronic antidepressant drug treatment, ECS, and lithium treatment in experimental animals, so far these changes have not provided a coherent explanation for the functional changes observed. It is the search for a coherent explanation that has prompted the formulation of the following hypothesis, (Grahame-Smith 1997). Mood depends on the numerical, structural, and functional homeostasis of sets of indeterminate synapses. This synaptic homeostasis depends on the normal physiological functioning of a neurotrophic system involving the monoamines, particularly 5-HT but perhaps also noradrenaline, which may act, along with other factors, to release neurotrophic factors such as BDNF. 5-HT can have important short term effects through biochemical cascades, altering post-translational factors to maintain immediate synaptic function, but it also has longer term synaptotrophic and neurotrophic effects, involving concerted and coherent changes in gene expression. The neurotrophic factors are also involved in enabling longer term neurotrophic effects through gene expression promoting synaptic cohesion and tine neuronal integrity. This homeostatic system is linely balanced and vulnerable to dysfunction. First, it must be able to react to external mental and physical stresses so as to maintain normality of function in those synapses involved in mood control. A genetically determined vulnerability would involve an inability to mount the neurobiological defence against stress (a neuroadaptive reponse), which normally allows psychological coping. Antidepressant treatment will act to enable the brain prone to a dysfunction of synaptic homeostasis to mount an adequate synaptotrophic and neurotrophic response, whether this be through the monoamine systems, as with the current antidepressant drugs, or through excitatory neurotransmitter systems secondarily affecting monoamine and/or neurotrophic factor function as seems likely with ECT. It is suggested that lithium, whatever its point-to-point molecular target, promotes the neurotrophic effects of 5-HT, reduces the vulnerabilty to synaptic (homeostatic) dysfunction, and thereby acts as a prophylactic in affective disorder. In order to investigate this hypothesis we have studied the expression of certain genes that might be involved in the neuroadaptive responses to the actions of antidepressant drugs, ECS, and lithium in rats, using protocols previously shown to affect 5-HT behavioural functions, In addition, we have manipulated brain 5-HT function with precursor treatment, agonists and antagonists. Others have similarly used these approaches in rats and mice to study neuroadaptive responses (see Duman et al, 1997 and Grahame-Smith, 1997 for full references). It has previously been shown that various antidepressant treatments alter the expression of some early immediate genes, and that 5-HT plays
S76
S.09 Treatment of the comorbidity
a role in these effects. Thus para-chloroamphetamine, which releases 5-HT, the 5-HT2* agonist DOI, and increases in extracellular brain 5HT concentrations all increase c-fos imrnunocytochemical expression in several brain areas. Several antidepressant drugs administered chronically, but not acutely, increase BDNF and TRKb mRNA in the hippocampus and block the down-regulation of BDNF mRNA in the hippocampus produced by restraint stress (Duman et el., 1997). Repeated ECS given in a way that enhances 5-HT behavioural functions causes a prolonged upregulation of BDNF mRNA in hippocampus and piriform cortex (ZetterstrGm et al 1998). Increasing brain 5-HT concentrations acutely increases BDNF gene expression in the frontal cortex but inhibits it in the dentate gyrus. ECS also causes an upregulation of mRNA expression of G-protein coupled potassium-channel subunits in the denture gyrus, an upregulation of the expression of certain potassium channel genes whose corresponding proteins are exclusively located on the dendrites of the granule cells, and increases the expression of the MAP2 mRNA in the dentate gyms (Pei et al., 1997 and 1998). MAP2 protein is more or less restricted to dendrites and these findings suggest that new dendritic elements may be formed during these treatments. Elevation of extracellular brain 5-HT concentrations by MAO inhibition and L-tryptophan administration stimulates mRNA expression of an additional dendritically localised gene ARC (active regulated cytoskeletal associated protein) in the cortex and the striatum and this effect is attenuated by ketanserin, a 5-HT2* antagonist. Evidence is therefore accumulating to suggest that antidepressant drugs and electroconvulsive shock (vis-B-vis ECT) might be acting acutely via neurotransmitter function, i.e. antidepressant drugs via noradrenaline and/or 5-HT, and ECT probably via excitatory neurotransmitters such as glutamate, to set in train neurotrophic and synaptotrophic processes that result in the formation or strengthening of synapses and neuronal networks necessary for the maintenance of normal mood. References 111 Duman. R. S.. G. R. Henineer and E. J. Nestler. 1997. A molecular and cellular theory bf dep&ion. Archives of General Psychiatry, 54 (7), 597606. [2] Graham&Smith, D. G., 1998. Chapter 7: Disorder of synaptic homeostasis as a canae of depression and a target for treabnent. In: M. Briley and S. Montgomery, eds. Antidepressant therapy at the dawn of the third millennium. London: Martin Duniti. [3] Pei, Q., P. I. W. Bnmet and T. S. C. Zetterstriim, 1998. Changes in mRNA abundance of micro tubular-associated proteins in the rat brain following electroconvulsive shock. Neuroreport, 9 (3), 39 l-394. [4] Pei, Q., et al., 1997. Differential effects of acute and chronic electroconvulsive shock on the abundance of messenger RNAs for voltage-dependent potassium channel subunits in the rat brain. Neuroscience, 78 (2), 343-350. [S] ZetterstrGm, T. S. C., Q. Pei and D. G. Grahame-Smith, 1998. Repeated electroconwlsive shock extends the duration of gene expression for BDNG’s rat brain compared with a single administration. Brain Research. Molecular Brain Research (In Press).
S.09 Treatment of the comorbidity and depressive states
Is.09.011 Do anxious
and depressive genetic factors?
of anxious
states share common
C.A. Prescott, KS. Kendler. Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatv, Virginia Commonwealth University, Richmond, Virginia, USA Clinical observation and prior research support a strong association between depressive and anxiety disorders. Family studies showing increased risk of anxiety disorders among the relatives of probands with is in major depression, and vice versalm3, suggest this co-occurrence part due to common etiological factors which are transmitted within families. Our research group previously reported on the comorbidity of major depression (MD) and generalized anxiety (GA) in a sample of 1,030 female twin pairs from the Commonwealth of Virginia, USA4. The two disorders were found to share the same genetic factors, and
of anxiousand
depressive states
these accounted for about 3&40% of the variation in liability for these disorders. The remaining variation in risk was due to individual-specific environmental factors. Half of this environmental variation was shared between MD and GA, and the remainder was disorder-specific. In 1993, we began a new, population-based longitudinal study of malemale and male-female twin pairs. In this paper we present preliminary results from an attempt to replicate in male twins our earlier findings on the etiology of the comorbidity of MD and GA in women. Method: Subjects are Caucasian adult male twins, born between 1940 and 1974, ascertained through the population-based Virginia T!vin Registry, and participating in a longitudinal study of common psychiatric and substance use disorders. Data for the current analyses were obtained in an ongoing second wave of interviews, scheduled to be completed in mid-1998. As of April 1998, data were available for analysis on about 50% of the anticipated final sample, including 375 identical (monozygotic or MZ) and 233 fraternal (dizygotic or DZ) twin pairs. Zygosity determinations were based on an algorithm of the twin’s responses to questionnaire items. The algorithm was validated by analysis of 15 highly informative DNA polymorphisms on a random sample of 174 twin pairs, and was found to correctly classify 94% of twin pairs. Diagnostic assessments were conducted using structured psychiatric interviews based on the Structured Clinical Interview for DSM-III-R (SCID’) but adapted to obtain information for both DSM-Ill-R and DSM-IV diagnoses. In-person interviews were conducted by interviewers who were blind to clinical information about the cotwin. Interviewers had a master’s degree in a mental-health related discipline or a bachelor’s degrees with at least 2 years relevant experience. The current analyses are based on DSM-IV defined MD. Because of concerns about low prevalences of GA, we use a less stringent definition of GA, requiring a 1-month duration and not requiring the anxiety be pervasive. Our analyses assume a liability/threshold model, in which there is a continuous, normally distributed, underlying liability of developing a disorder, and individuals who exceed a threshold manifest the disorder, while those below the threshold do not. The twin model includes three sources of population variation in liability: additive genetic effects (A); family or “common” environment (C); and individual-specific environment and measurement error(E). The estimates for the three components derive from comparisons of the similarity of monozygotic (MZ) and dizygotic (DZ) twin pairs within and across diagnoses. MZ and DZ pairs are assumed to have equally similar family environments, but different degrees of genetic similarity, with MZ pairs being perfectly correlated, but DZ pairs correlated .5 on average. Thus, if the two types of twin pairs are equally similar in their resemblance for a characteristic, common environmental factors are inferred to be operating. To the degree that MZ twin pairs are more similar than DZ pairs, we can infer the etiological influence of genetic factors. Results: Lifetime prevalences were 29% for MD and 12% for GA. The pair correlations for MD and GA were modest, but for both disorders, MZ twin pair resemblance exceeds that among DZ pairs for both MD (rMz = .22, rDz = .16) And GA (rm = .25, r~z = .16), although the differences were not statistically significant. The lifetime co-occurrence of MD and GA in this sample was substantial. Among men with a history of GA, nearly three-quarters had experienced an episode of MD. The correlation in shared liability for these disorders was estimated as .6l. To estimate the sources of this overlapping liability, bivariate twin models use MZ-DZ differences in the cross-twin cross-disorder correlations. Among MZ pairs, MD in one twin was correlated .34 with GA in the cotwin. This value actually exceeds the cross-twin within-disorder correlations for both disorders, suggesting that the cotwin of an MZ twin with a history of MD is equally likely to develop GA or MD. In contrast, among DZ pairs, MD in one twin was correlated near zero with GA in the cotwin. Taken together, these data suggest that the overlapping liability is due in part to genetic but not common environmental sources. Formal bivariate twin models applied to these data supported this suggestion. The best fitting model was one which modeled all the genetic sources of variation in MD and GA as shared by the two disorders. The remaining variation was estimated as due to individual-specific factors, about half of which was shared by the two disorders, and the remainder was disorder-specific.