Social cognitive and affective neuroscience, Jan 15, 2015
The traditional concept of "categorical" psychiatric disorders has been challenged as m... more The traditional concept of "categorical" psychiatric disorders has been challenged as many of the symptoms display a continuous distribution in the general population. We suggest that this is the case for emotional dysregulation, a key component in several categorical psychiatric disorder constructs. We used voxel based MRI morphometry (VBM) in healthy human subjects (n=87) to study how self-reported subclinical symptoms associated with emotional dysregulation relate to brain regions assumed to be critical for emotion regulation. In order to measure a pure emotional dysregulation we also corrected for subclinical symptoms of non-emotional attentional dysregulation. We show that such subclinical emotional symptoms correlate negatively with the gray matter volume of lateral orbitofrontal cortex (lObfc) bilaterally - a region assumed to be critical for emotion regulation and dysfunctional in psychiatric disorders involving emotional dysregulation. Importantly, this effect is ...
Inflammation has been linked to the pathophysiology of bipolar disorder based on studies of infla... more Inflammation has been linked to the pathophysiology of bipolar disorder based on studies of inflammation markers, such as cytokine concentrations, in plasma and serum samples from cases and controls. However, peripheral measurements of cytokines do not readily translate to immunological activity in the brain. The aim of the present study was to study brain immune and inflammatory activity. To this end, we analyzed cytokines in cerebrospinal fluid from 121 euthymic bipolar disorder patients and 71 age and sex matched control subjects. Concentrations of 11 different cytokines were determined using immunoassays. Cerebrospinal fluid IL-8 concentrations were significantly higher in patients as compared to controls. The other cytokines measured were only detectable in part of the sample. IL-8 concentrations were positively associated to lithium- and antipsychotic treatment. The findings might reflect immune aberrations in bipolar disorder, or be due to the effects of medication.
Polycystic ovary syndrome (PCOS) is a common hyperandrogenic endocrine disorder affecting women o... more Polycystic ovary syndrome (PCOS) is a common hyperandrogenic endocrine disorder affecting women of fertile age. The aim of this study was to survey whether the rate of clinical psychiatric disorders in PCOS differs from the normal population. Women with PCOS (n=49) meeting the Rotterdam criteria for PCOS, and 49 age-matched controls identified from the population registry, were recruited. Trained clinicians used the MINI International Neuropsychiatric Interview to establish lifetime occurrence of Axis I DSM diagnoses. Serum-testosterone and sex hormone binding globulin were analyzed. Women with PCOS had higher lifetime incidence of depressive episodes, social phobia, and eating disorders than controls. Suicide attempts were seven times more common in the PCOS group than in the controls. Current as well as lifetime use of antidepressants and anxiolytic drugs were more common in the PCOS group. Previous studies have found that PCOS is associated with decreased quality of life and self-rated mental symptoms. This study demonstrates that PCOS is also linked to psychiatric syndromes as verified by structured clinical assessments. The clinical implication of this study is that clinicians treating women with PCOS should be aware that these women are a high risk group for common affective and anxiety disorders as well as suicide attempts.
Blood-cerebrospinal barrier (BCB) dysfunction has previously been shown in subjects with schizoph... more Blood-cerebrospinal barrier (BCB) dysfunction has previously been shown in subjects with schizophrenia and depressed patients with attempted suicide. Bipolar disorder (BPD) shares clinical features with both these disorders, but it is unknown if the integrity of the BCB is altered also in BPD. To assess if BCB function in BPD we surveyed 134 mood-stabilized BPD patients and 86 healthy controls. Serum and cerebrospinal fluid (CSF) samples were collected and analyzed for albumin concentration by immunonephelometry. CSF/serum albumin ratio, an established measure of BCB function, was significantly elevated in BPD patients as compared to controls. After stratifying patients according to diagnostic subtype, BPD I patients had the highest CSF/serum albumin ratios. Moreover, BPD patients on antipsychotic treatment had higher CSF/serum albumin ratio than BPD patients on other treatments. When excluding BPD patients on antipsychotic treatment the difference in CSF/serum albumin ratio between the BPD and control groups disappeared. In conclusion, antipsychotic treatment in BPD is associated with elevated CSF/serum albumin ratio, tentatively as a sign of impaired BCB function. Whether this elevation is caused by antipsychotic treatment or is associated with a certain subtype of BPD, requiring antipsychotic treatment, remains to be determined.
Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The et... more Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for BD. To investigate this hypothesis, we sampled CSF from 133 patients with BD and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-type fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, although the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs.
Bipolar disorder is a common psychiatric mood disorder that is defined by recurrent episodes of a... more Bipolar disorder is a common psychiatric mood disorder that is defined by recurrent episodes of abnormally elevated mood and depression. Progressive structural brain changes in individuals with bipolar disorder have been suggested to be associated with defects in the secretion of neurotrophic factors. We sought to assess how the regulated secretory pathway in the brain is affected in patients with bipolar disorder by measuring chromogranin B and secretogranin II, which are 2 cerebrospinal fluid (CSF) biological markers for this process. We measured the concentrations of chromogranin B (peptide 439-451) and secretogranin II (peptide 154-165) in the CSF of patients with well-defined bipolar disorder and healthy controls. The lifetime severity of bipolar disorder was rated using the Clinical Global Impression (CGI) scale. We included 126 patients with bipolar disorder and 71 healthy controls in our analysis. Concentrations of secretogranin II were significantly lower in patients with bipolar disorder type I than in healthy controls. The reduction was most pronounced in patients with high CGI scores (i.e., severe disease). The cross-sectional design of the current study limits the ability to pinpoint the causalities behind the observed associations. This study shows that the CSF marker secretogranin II has the potential to act as a biological marker for severe forms of bipolar disorder. Our findings indicate that patients with bipolar disorder possess defects in the regulatory secretory pathway, which may be of relevance to the progressive structural brain changes seen in those with severe forms of the disease.
Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signallin... more Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signalling depending on the dopaminergic tone. (-)-OSU6162 and ACR16 appear to possess such a profile. They have been proposed to act as partial dopamine receptor agonists or as antagonists with preferential action on dopaminergic autoreceptors. Previous studies have shown either stimulation or inhibition of behaviour in response to (-)-OSU6162 and ACR16, which has been suggested to reflect their dual effects on dopaminergic signalling. The aims of the present work are to (1) examine the relation between behavioural response to these drugs and activity baseline, and (2) test the suggested mechanisms of action by means of close comparisons with the known partial D2-receptor agonists (-)-3-PPP and aripiprazole, and the D2 autoreceptor preferring antagonist amisulpride with respect to effects on behaviour. From the results of these experiments it can be concluded that: (1) The direction of the response to (-)-OSU6162 and ACR16 is dependent on activity baseline, which in turn, under physiological conditions, is determined primarily by test arena size of and degree of habituation to the environment. (2) The effects of (-)-OSU6162 and ACR16 cannot be explained on the basis of either partial dopamine receptor agonism or preferential dopamine autoreceptor antagonism. Nevertheless, the current data suggest at least two different D2-receptor-associated targets which mediate opposite effects on activity. This result fits in with a mechanism proposed from a recent in vitro study, according to which (-)-OSU6162 has a dual action on dopamine D2 receptors, (a) an allosteric effect causing an enhanced response to dopamine, and (b) the previously proposed orthosteric effect antagonizing the action of dopamine.
Eight monophenolic cis- and trans-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines have ... more Eight monophenolic cis- and trans-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines have been synthesized and tested for central dopamine- and serotonin-receptor stimulating activity, using biochemical and behavioral tests in rats. The trans-7-, -8-, and -9-hydroxy isomers all elicited central pre- and postsynaptic dopaminergic receptor stimulation, while the trans-10-hydroxy isomer was devoid of dopaminergic activity but instead showed central serotoninergic activity. In all four isomeric pairs, the trans isomers were consistently much more potent than their corresponding cis analogues. The apparent presynaptic selectivity of the dopaminergic cis isomer cis-9-hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline could not be confirmed due to the toxic properties of this compound. Central dopamine receptors (autoreceptors and postsynaptic receptors) can accept dopaminergic compounds with one of possibly two N-substituents being larger than n-propyl, if this substituent is properly oriented in relation to the rest of the molecule.
The objective of the described research effort was to identify a novel serotonin and norepinephri... more The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.
Social cognitive and affective neuroscience, Jan 15, 2015
The traditional concept of "categorical" psychiatric disorders has been challenged as m... more The traditional concept of "categorical" psychiatric disorders has been challenged as many of the symptoms display a continuous distribution in the general population. We suggest that this is the case for emotional dysregulation, a key component in several categorical psychiatric disorder constructs. We used voxel based MRI morphometry (VBM) in healthy human subjects (n=87) to study how self-reported subclinical symptoms associated with emotional dysregulation relate to brain regions assumed to be critical for emotion regulation. In order to measure a pure emotional dysregulation we also corrected for subclinical symptoms of non-emotional attentional dysregulation. We show that such subclinical emotional symptoms correlate negatively with the gray matter volume of lateral orbitofrontal cortex (lObfc) bilaterally - a region assumed to be critical for emotion regulation and dysfunctional in psychiatric disorders involving emotional dysregulation. Importantly, this effect is ...
Inflammation has been linked to the pathophysiology of bipolar disorder based on studies of infla... more Inflammation has been linked to the pathophysiology of bipolar disorder based on studies of inflammation markers, such as cytokine concentrations, in plasma and serum samples from cases and controls. However, peripheral measurements of cytokines do not readily translate to immunological activity in the brain. The aim of the present study was to study brain immune and inflammatory activity. To this end, we analyzed cytokines in cerebrospinal fluid from 121 euthymic bipolar disorder patients and 71 age and sex matched control subjects. Concentrations of 11 different cytokines were determined using immunoassays. Cerebrospinal fluid IL-8 concentrations were significantly higher in patients as compared to controls. The other cytokines measured were only detectable in part of the sample. IL-8 concentrations were positively associated to lithium- and antipsychotic treatment. The findings might reflect immune aberrations in bipolar disorder, or be due to the effects of medication.
Polycystic ovary syndrome (PCOS) is a common hyperandrogenic endocrine disorder affecting women o... more Polycystic ovary syndrome (PCOS) is a common hyperandrogenic endocrine disorder affecting women of fertile age. The aim of this study was to survey whether the rate of clinical psychiatric disorders in PCOS differs from the normal population. Women with PCOS (n=49) meeting the Rotterdam criteria for PCOS, and 49 age-matched controls identified from the population registry, were recruited. Trained clinicians used the MINI International Neuropsychiatric Interview to establish lifetime occurrence of Axis I DSM diagnoses. Serum-testosterone and sex hormone binding globulin were analyzed. Women with PCOS had higher lifetime incidence of depressive episodes, social phobia, and eating disorders than controls. Suicide attempts were seven times more common in the PCOS group than in the controls. Current as well as lifetime use of antidepressants and anxiolytic drugs were more common in the PCOS group. Previous studies have found that PCOS is associated with decreased quality of life and self-rated mental symptoms. This study demonstrates that PCOS is also linked to psychiatric syndromes as verified by structured clinical assessments. The clinical implication of this study is that clinicians treating women with PCOS should be aware that these women are a high risk group for common affective and anxiety disorders as well as suicide attempts.
Blood-cerebrospinal barrier (BCB) dysfunction has previously been shown in subjects with schizoph... more Blood-cerebrospinal barrier (BCB) dysfunction has previously been shown in subjects with schizophrenia and depressed patients with attempted suicide. Bipolar disorder (BPD) shares clinical features with both these disorders, but it is unknown if the integrity of the BCB is altered also in BPD. To assess if BCB function in BPD we surveyed 134 mood-stabilized BPD patients and 86 healthy controls. Serum and cerebrospinal fluid (CSF) samples were collected and analyzed for albumin concentration by immunonephelometry. CSF/serum albumin ratio, an established measure of BCB function, was significantly elevated in BPD patients as compared to controls. After stratifying patients according to diagnostic subtype, BPD I patients had the highest CSF/serum albumin ratios. Moreover, BPD patients on antipsychotic treatment had higher CSF/serum albumin ratio than BPD patients on other treatments. When excluding BPD patients on antipsychotic treatment the difference in CSF/serum albumin ratio between the BPD and control groups disappeared. In conclusion, antipsychotic treatment in BPD is associated with elevated CSF/serum albumin ratio, tentatively as a sign of impaired BCB function. Whether this elevation is caused by antipsychotic treatment or is associated with a certain subtype of BPD, requiring antipsychotic treatment, remains to be determined.
Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The et... more Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for BD. To investigate this hypothesis, we sampled CSF from 133 patients with BD and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-type fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, although the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs.
Bipolar disorder is a common psychiatric mood disorder that is defined by recurrent episodes of a... more Bipolar disorder is a common psychiatric mood disorder that is defined by recurrent episodes of abnormally elevated mood and depression. Progressive structural brain changes in individuals with bipolar disorder have been suggested to be associated with defects in the secretion of neurotrophic factors. We sought to assess how the regulated secretory pathway in the brain is affected in patients with bipolar disorder by measuring chromogranin B and secretogranin II, which are 2 cerebrospinal fluid (CSF) biological markers for this process. We measured the concentrations of chromogranin B (peptide 439-451) and secretogranin II (peptide 154-165) in the CSF of patients with well-defined bipolar disorder and healthy controls. The lifetime severity of bipolar disorder was rated using the Clinical Global Impression (CGI) scale. We included 126 patients with bipolar disorder and 71 healthy controls in our analysis. Concentrations of secretogranin II were significantly lower in patients with bipolar disorder type I than in healthy controls. The reduction was most pronounced in patients with high CGI scores (i.e., severe disease). The cross-sectional design of the current study limits the ability to pinpoint the causalities behind the observed associations. This study shows that the CSF marker secretogranin II has the potential to act as a biological marker for severe forms of bipolar disorder. Our findings indicate that patients with bipolar disorder possess defects in the regulatory secretory pathway, which may be of relevance to the progressive structural brain changes seen in those with severe forms of the disease.
Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signallin... more Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signalling depending on the dopaminergic tone. (-)-OSU6162 and ACR16 appear to possess such a profile. They have been proposed to act as partial dopamine receptor agonists or as antagonists with preferential action on dopaminergic autoreceptors. Previous studies have shown either stimulation or inhibition of behaviour in response to (-)-OSU6162 and ACR16, which has been suggested to reflect their dual effects on dopaminergic signalling. The aims of the present work are to (1) examine the relation between behavioural response to these drugs and activity baseline, and (2) test the suggested mechanisms of action by means of close comparisons with the known partial D2-receptor agonists (-)-3-PPP and aripiprazole, and the D2 autoreceptor preferring antagonist amisulpride with respect to effects on behaviour. From the results of these experiments it can be concluded that: (1) The direction of the response to (-)-OSU6162 and ACR16 is dependent on activity baseline, which in turn, under physiological conditions, is determined primarily by test arena size of and degree of habituation to the environment. (2) The effects of (-)-OSU6162 and ACR16 cannot be explained on the basis of either partial dopamine receptor agonism or preferential dopamine autoreceptor antagonism. Nevertheless, the current data suggest at least two different D2-receptor-associated targets which mediate opposite effects on activity. This result fits in with a mechanism proposed from a recent in vitro study, according to which (-)-OSU6162 has a dual action on dopamine D2 receptors, (a) an allosteric effect causing an enhanced response to dopamine, and (b) the previously proposed orthosteric effect antagonizing the action of dopamine.
Eight monophenolic cis- and trans-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines have ... more Eight monophenolic cis- and trans-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines have been synthesized and tested for central dopamine- and serotonin-receptor stimulating activity, using biochemical and behavioral tests in rats. The trans-7-, -8-, and -9-hydroxy isomers all elicited central pre- and postsynaptic dopaminergic receptor stimulation, while the trans-10-hydroxy isomer was devoid of dopaminergic activity but instead showed central serotoninergic activity. In all four isomeric pairs, the trans isomers were consistently much more potent than their corresponding cis analogues. The apparent presynaptic selectivity of the dopaminergic cis isomer cis-9-hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline could not be confirmed due to the toxic properties of this compound. Central dopamine receptors (autoreceptors and postsynaptic receptors) can accept dopaminergic compounds with one of possibly two N-substituents being larger than n-propyl, if this substituent is properly oriented in relation to the rest of the molecule.
The objective of the described research effort was to identify a novel serotonin and norepinephri... more The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.
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Papers by Anette Johansson