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Neuroendocrine studies in patients with affective disorders
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Affective disorders are common and a major cause for increased disability and mortality worldwide. Exogenous stressors and biological variables, including neuroendocrine factors, are assumed to contribute to an increased vulnerability to mood dysregulation. Affective disorders are highly heterogeneous and different neuroendocrine systems may play differential roles in the phenotypic expression of affective disorders in men and women.

Aims: The overall aim of this thesis was to study three neuroendocrine systems in relation to underlying behavioral endophenotypes (personality traits, self-directed and interpersonal violence, and psychiatric symptoms) in patients with affective disorders.

Methods: In Study I oxytocin plasma levels were assessed in 101 general psychiatric outpatients and followed-up in 36 patients after one month. Patients underwent diagnostic, symptomatic, and personality trait assessments.

In Study II insulin and glucagon levels in plasma and cerebrospinal fluid (CSF) were assessed in 28 patients hospitalized after a recent suicide attempt and 19 healthy controls. Study persons were assessed regarding lifetime violence expression, psychiatric diagnoses and symptoms.

In Study III serum levels of allopregnanolone, progesterone and estradiol were assessed in 14 women with severe postpartum depression and psychosis who, as previously reported, responded with rapid symptom remission during sublingual estradiol treatment. Hormonal and symptomatic assessment were performed before and after 4 weeks of estradiol treatment. 28 healthy postpartum controls were included for baseline comparison.

Results: I) Plasma oxytocin levels were positively associated with personality traits of impulsiveness (monotony avoidance) and negative emotionality (psychic anxiety) with potential gender differences.

II) Patients after suicide attempt had higher insulin (plasma and CSF) and lower glucagon levels (CSF) than healthy controls. Insulin levels (plasma and CSF) were higher and glucagon levels (plasma) were lower in patients and controls with higher levels of prior violence expression.

III) Serum allopregnanolone decreased in women with postpartum depression and psychosis during estradiol treatment. The ratio between allopregnanolone and progesterone was significantly lower in patients than in healthy controls at baseline and it remained unchanged after symptom remission.

Conclusion: Behavioral endophenotypes, rather than categorical diagnoses, of affective disorders were associated with neuroendocrine variation in three different cohorts of patients with affective disorder. Hormonal variation pointed towards an association with trait, rather than state like facets of affective behavior, constituting potential vulnerability markers for affective dysregulation.

Abstract [sv]

Världen över drabbas 350 miljoner människor av unipolära depressioner och bipolära sjukdomar (affektiva sjukdomar). Patienter med affektiva sjukdomar dör cirka femton år tidigare på grund av kroppsliga sjukdomar och suicid. Upp till varannan patient försöker ta sitt liv och lika många svarar inte på behandling eller får återfall trots behandling. Det är mycket vanligt med sociala svårigheter som påverkar familj- och arbetsliv. Medan män har större risk att ta sina liv löper kvinnor ökad risk att göra suicidförsök och att utveckla depression. Efter en förlossning är risken att drabbas av svåra affektiva sjukdomar förhöjd som kan uttrycka sig i form av svåra depressioner, manier eller psykoser. Dessa tillstånd ökar risken för att modern tar sitt liv och i sällsynta fall även barnets liv.

Vissa människor är särskilt sårbara att utveckla affektiva sjukdomar. Sårbarheten påverkas av genetiska faktorer och livshändelser. Det är dock oklart hur patienternas emotionella, kognitiva och kroppsliga symtom uppstår och hur dessa hänger ihop med förändringar i hjärnan och generna. Ökad kunskap om dessa processer skulle sannolikt förbättra möjligheten att behandla och förebygga affektiva sjukdomar.

Patienter i gruppen affektiva sjukdomar är väldigt olika; de skiljer sig avseende emotionella, kognitiva och kroppsliga symtom, avseende risker för sjukdomsutveckling samt återfallsrisk och behandlingssvar. Ett sätt att försöka koppla sjukdomstecken och förändringar i hjärnan är att undersöka mer enhetliga grupper av patienter som till exempel patienter som gjort suicidförsök eller kvinnor efter förlossningen. Ett annat sätt är att undersöka särskilda underliggande aspekter som till exempel personlighet.

Hos många patienter med psykisk sjukdom har man hittat förändringar i stressystemet. Vid stress påverkas bland annat hormonella system. Hormoner påverkar inte enbart kroppens men även hjärnans funktion. Genom att undersöka kopplingen av hormonella faktorer med kroppsliga, mentala och beteendeuttryck kan man indirekt dra slutsatser om hjärnans funktion vid affektiva sjukdomar.

I den här avhandlingen har vi undersökt hur tre olika hormonella system är kopplade till särskilda underliggande aspekter av affektiva sjukdomar. Avhandlingen består av tre olika studier.

I den första frågade vi oss om oxytocin är kopplad till personlighetsdrag som har relevans för patienternas sociala svårigheter. Detta undersökte vi i en stor grupp av öppenvårdspatienter med olika psykiska sjukdomar.

I den andra ville vi veta om patienter som hade gjort självmordsförsök hade förändrade nivåer av insulin och glukagon och om detta var kopplad till våldsamt beteende.

I den tredje studien undersökte vi om kvinnor med svår depression och psykos efter förlossningen uppvisade förändringar av allopregnanolon och progesteron. Dessutom kunde vi undersöka förändringar av dessa hormon under behandling med estradiol när kvinnorna hade tillfrisknat.

I den första studien visade vi att patienter med psykiska sjukdomar som hade mer impulsiva och negativ emotionella personlighetsdrag hade högre oxytocin nivåer. Dessa patienter hade särskilda drag av ångest och var mer extroverta. Möjligen var dessa samband särskild tydliga hos män.

I den andra studien visade vi att patienter som hade gjort självmordsförsök hade högre nivåer av insulin i blodet och i ryggmärgsvätskan än friska kontroll-personer. Dessutom hade de lägre nivåer av glukagon i blodet. Högre nivåer av insulin och lägre nivåer av glukagon var kopplade till självrapporterat interpersonellt våld sedan femton års ålder hos patienter och friska kontroller.

I den tredje studien visade vi att allopregnanolon minskade under estradiol behandling för postpartum depression och postpartum psykos. Patienterna uppvisade både före och under behandlingen förändringar i relationen mellan allopregnanolon och progesteron jämfört med friska kvinnor.

Sammanfattningsvis tyder resultaten på att särskilda underliggande aspekter av affektiva sjukdomar är kopplade med förändringar i hormonella system. Dessa förändringar ter sig vara kopplade med långvariga drag hellre än akuta sjukdomsuttryck och kan på så sätt tyda på sårbarhetsfaktorer för affektiva sjukdomar. Resultaten bidrar till ökad förståelse om särskilda hormonella aspekter hos specifika grupper av personer med affektiva sjukdomar.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2019. , p. 74
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2010
Keywords [en]
Affective disorder, Suicide attempt, Postpartum depression, Postpartum psychosis, Personality traits, Violence, Oxytocin, Insulin, Glucagon, Allopregnanolone, Progesterone, Estradiol
National Category
Psychiatry
Identifiers
URN: urn:nbn:se:umu:diva-156829ISBN: 978-91-7855-015-9 (print)OAI: oai:DiVA.org:umu-156829DiVA, id: diva2:1292460
Public defence
2019-03-28, Föreläsningssal A, Psykiatriska kliniken, Målpunkt F, Plan 0, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2019-03-07 Created: 2019-02-28 Last updated: 2019-03-06Bibliographically approved
List of papers
1. Plasma oxytocin and personality traits in psychiatric outpatients
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2015 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 57, p. 102-110Article in journal (Refereed) Published
Abstract [en]

The oxytocin system is regarded as being of relevance for social interaction. In spite of this, very few studies have investigated the relationship between oxytocin and personality traits in clinical psychiatric populations. We assessed the relationship between personality traits and plasma oxytocin levels in a population of 101 medication-free psychiatric outpatients (men = 37, women = 64). We used the Karolinska Scale of Personality (KSP) and diagnostic and symptomatic testing. Plasma oxytocin levels were analysed with a specific radioimmunoassay at inclusion and after one month for testing of stability. Plasma oxytocin levels were stable over time and did not differ between patients with or without personality disorders, nor were they related to severity of depressive or anxiety symptoms. The KSP factors Impulsiveness and Negative Emotionality were significant independent predictors of plasma oxytocin. A subscale analysis of these personality factors showed significant positive correlations between baseline plasma oxytocin and the KSP subscales monotony avoidance and psychic anxiety. The significant association between the KSP factor Impulsiveness and oxytocin levels observed at baseline was observed also one month later in men. These findings suggest that personality traits such as Impulsiveness and Negative emotionality which are linked to social functioning in several psychiatric disorders seem to be associated with endogenous plasma oxytocin levels. These variations in oxytocin levels might have an impact on social sensitivity or social motivation with possible gender differences.

Keywords
Oxytocin, Personality traits, Personality disorder, Mood disorder, Extraversion, Anxiety
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-106490 (URN)10.1016/j.psyneuen.2015.04.003 (DOI)000355707000010 ()25910979 (PubMedID)
Available from: 2015-07-16 Created: 2015-07-14 Last updated: 2019-02-28Bibliographically approved
2. Insulin and glucagon in plasma and cerebrospinal fluid in suicide attempters and healthy controls
Open this publication in new window or tab >>Insulin and glucagon in plasma and cerebrospinal fluid in suicide attempters and healthy controls
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2017 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 81, p. 1-7Article in journal (Refereed) Published
Abstract [en]

Mental disorders and related behaviors such as suicidality and violence have been associated to dysregulation of e g carbohydrate metabolism. We hypothesized that patients after suicide attempt, compared to healthy controls, would have higher insulin and lower glucagon levels in plasma and cerebrospinal fluid and that these changes would be associated to violent behavior. Twenty-eight medication-free patients (10 women, 18 men), hospitalized after suicide attempt, and 19 healthy controls (7 women, 12 men) were recruited with the aim to study risk factors for suicidal behavior. Psychological/psychiatric assessment was performed with SCID I and II or the SCID interview for healthy volunteers respectively, the Karolinska Interpersonal Violence Scale (KIVS) for assessment of lifetime violence expression behavior, the Montgomery-Asberg-Depression-Scale (MADRS) and the Comprehensive Psychological Rating Scale (CPRS) for symptomatic assessment of depression and appetite. Fasting levels of insulin and glucagon were measured in plasma (P) and cerebrospinal fluid (CSF). Suicide attempters had higher insulin- and lower glucagon-levels in plasma- and CSF compared to controls. Except for P-glucagon these associations remained significant after adjusting for age and/or BMI. Patients reported significantly more expressed interpersonal violence compared to healthy volunteers. Expressed violence was significantly positively correlated with P- and CSF-insulin and showed a significant negative correlation with P-glucagon in study participants. These findings confirm and extend prior reports that higher insulin and lower glucagon levels in plasma and cerebrospinal fluid are associated with suicidal behavior pointing towards a potential autonomic dysregulation in the control of insulin and glucagon secretion in suicidal patients. 

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Suicide attempt, Insulin, Glucagon, Aggression, Violence, Depression
National Category
Psychiatry Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-137977 (URN)10.1016/j.psyneuen.2017.03.019 (DOI)000404815200001 ()28391069 (PubMedID)
Note

Errata: Bendix M, Uvnäs-Moberg K, Petersson M, Kaldo V, Åsberg M, Jokinen J. Corrigendum to “Insulin and glucagon in plasma and cerebrospinal fluid in suicide attempters and healthy controls” [Psychoneuroendocrinology 81 (2017) 1–7]. Psychoneuroendocrinology (2018) 94, 168. DOI: 10.1016/j.psyneuen.2018.04.014

Available from: 2017-08-02 Created: 2017-08-02 Last updated: 2019-03-06Bibliographically approved
3. Corrigendum to "Insulin and glucagon in plasma and cerebrospinal fluid in suicide attempters and healthy controls" [Psychoneuroendocrinology 81 (2017) 1-7]
Open this publication in new window or tab >>Corrigendum to "Insulin and glucagon in plasma and cerebrospinal fluid in suicide attempters and healthy controls" [Psychoneuroendocrinology 81 (2017) 1-7]
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2018 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 94, article id 168Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-156822 (URN)10.1016/j.psyneuen.2018.04.014 (DOI)000436913400019 ()29731382 (PubMedID)
Note

DOI of original article: 10.1016/j.psyneuen.2017.03.019

Available from: 2019-02-28 Created: 2019-02-28 Last updated: 2019-03-06Bibliographically approved
4. Allopregnanolone and progesterone inestradiol treated severe postpartumdepression and psychosis
Open this publication in new window or tab >>Allopregnanolone and progesterone inestradiol treated severe postpartumdepression and psychosis
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background

Postpartum affective disorders may be associated with dysregulation of gonadal steroids. We investigated peripheral levels of allopregnanolone and progesterone in a combined group of women with postpartum onset of severe depression and psychosis who, as previously reported, responded with rapid symptom remission during sublingual estradiol treatment. The aim was to assess differences in allopregnanolone and progesterone between patients and healthy controls at baseline, and hormonal changes during estradiol treatment and symptom remission in patients.

Methods

Allopregnanolone and progesterone in serum were analyzed with radioimmunoassay before and four weeks after initiation of sublingual estradiol treatment in ten women with postpartum depression and four women with postpartum psychosis (ICD-10). Twenty-eight healthy postpartum controls were included for baseline comparison.

Results

Allopregnanolone declined significantly during estradiol treatment while there was a trend for lower baseline allopregnanolone levels in patients compared with healthy postpartum controls. The ratio between allopregnanolone and progesterone was significantly lower in patients compared with controls and it remained unchanged after clinical recovery.

Limitations

This study is a secondary analysis of two estradiol treatment studies based on availability of samples for the analysis of allopregnanolone. Healthy controls were assessed earlier after birth. Data on potential confounders (somatic health, breastfeeding, other medication) were not available.

Conclusions

Clinical recovery of severe postpartum depression and psychosis during estradiol treatment does not seem to depend on increasing levels of allopregnanolone. Differences in progesterone metabolism may constitute a risk factor for severe postnatal affective dysregulation.

Highlights

- Allopregnanolone decreased during estradiol treatment in postpartum depression and psychosis.

- The Allopregnanolone/Progesterone ratio was lower in patients compared with controls

- Change in neurosteroid metabolism may be risk factor for postnatal affective dysregulation

Keywords
postpartum depression, postpartum psychosis, allopregnanolone, progesterone, estradiol, estradiol treatment
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-156823 (URN)
Available from: 2019-02-28 Created: 2019-02-28 Last updated: 2019-03-06

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