The Munich vulnerability study on affective disorders: premorbid polysomnographic profile of affected high-risk probands.

BACKGROUND: The most characteristic alterations in the sleep electroencephalogram (EEG) during major depression are a shortened latency to rapid eye movement (REM) sleep and an elevated REM density. Because these changes persist in remission, they might represent vulnerability markers. To identify vulnerability markers, we investigated premorbid sleep EEG parameters in healthy high-risk probands (HRPs) with a positive family history of affective disorders. METHODS: We identified 136 depressed inpatients from referrals to our hospital who had first-degree relatives with an affective disorder as well as first-degree relatives with no current or lifetime history of psychiatric disorders. The latter (the HRP group) were investigated by polysomnography. During the follow-up period, 20 HRPs developed an affective disorder. Their premorbid sleep data were analyzed. RESULTS: Premorbid sleep EEG of affected HRPs showed an increased REM density (total night and first REM period) compared with the control group without personal or family history of a psychiatric disorder. CONCLUSIONS: Increased REM density can be observed not only in patients with depression, but also in their healthy relatives. Moreover, it is predictive for the onset of a psychiatric disorder. Therefore, it can be recommended as a possible endophenotype of these diseases.     

The Munich vulnerability study on affective disorders: overview of the cross-sectional observations at index investigation

Background: An altered nocturnal sleep pattern and a dysfunction of the hypothalamic–pituitary–adrenocortical system are neurobiological abnormalities typical for depression. A persistence of these neurobiological alterations during remission has been shown to be associated with an increased risk for a relapse. However, it remains unclear whether these persisting abnormalities are trait markers indicative of an increased vulnerability for affective disorders or only represent biological scars acquired during past episodes. Thus, respective examinations need to be performed in the premorbid state in order to answer this open question. Methods: In the present article we have summarized the various results of the index investigation of a prospectively designed study in which we investigated 54 healthy first-degree relatives (high-risk probands; HRPs) of patients with an affective disorder using polysomnography, the combined dexamethasone corticotropine-releasing hormone (DEX-CRH) test and psychometric measurements. Results: In the cross-sectional part of this study the HRPs, as a group, exhibited a depression-like sleep EEG profile and DEX-CRH test result, while their psychometric profile was characterized by elevated scores on the measures Rigidity and Autonomic lability. On an individual level, 35% of the HRPs were identified as conspicuous in at least two of the three areas under investigation. Conclusions: The question of whether these abnormalities do indeed reflect trait markers indicative of an increased vulnerability for depression will be answered by the longitudinal part of the study that allows for the retrospective identification of the premorbid status of those HRPs who develop an affective disorder during the follow-up period.     

The Munich vulnerability study on affective disorders: premorbid neuroendocrine profile of affected high-risk probands

One of the most characteristic alterations in depression is a disturbed regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. A function test combining the pre-treatment of 1.5 mg dexamethasone (DEX) with a challenge of 100 microg corticotropin-releasing hormone (CRH) reveals a pathological increase in the adrenocorticotropin and cortisol release in patients with major depression. These changes partially persist after successful treatment with remission and therefore, might represent trait or vulnerability markers. To further address this question, we were investigating the premorbid neuroendocrine profile of 74 healthy high-risk probands (HRPs) with a positive family history for affective disorders. The aim was to identify premorbid vulnerability factors. During the observation period, 19 HRPs developed an affective disorder. Their premorbid DEX/CRH test results were compared with 19 age- and sex matched controls. No significant differences could be observed between these two groups. Our results suggest that a dysregulated HPA system indicated by this function test can rather be regarded as a neurobiological scar developing during the course of affective disorders.     

The Munich vulnerability study on affective disorders: microstructure of sleep in high-risk subjects

Vulnerability markers for affective disorders have focused on stress hormone regulation and sleep. Among rapid eye movement (REM) sleep, increased REM pressure and elevated REM density are promising candidates for vulnerability markers. Regarding nonREM sleep, a deficit in amount of and latency until slow wave sleep during the first half of the night is a characteristic for depression. To further elucidate whether changes in the microstructure of sleep may serve as vulnerability markers we investigated the premorbid sleep composition in 21 healthy high-risk proband (HRPs) with a positive family history for affective disorders and compared HRPs with a control group of healthy subjects (HCs) without personal and family history for psychiatric disorders. The sleep electroencephalogram (EEG) was conventionally scored and submitted to a quantitative EEG analysis. The main difference in sleep characteristics between HRPs and HCs was an abnormally increased REM density. Differences in the spectral composition of sleep EEG were restricted to an increased power in the sigma frequency range. Since the HRP group comprised six unrelated and 15 related subjects we controlled for sibling effects. We could replicate the increased REM density in the group of HRPs whereas elevated power in the low sigma frequencies persisted only with approaching significance. The present study further supports elevated REM density as putative vulnerability marker for affective disorders. However, sleep EEG in our group of HRPs did not show slow wave sleep abnormalities. Ongoing follow up investigations of HRPs will clarify whether the observed increase in sigma EEG activity during nonREM sleep is of clinical relevance with respect to the likelihood to develop an affective disorder.     

The Munich Vulnerability Study on Affective Disorders: stability of polysomnographic findings over time.

BACKGROUND: Some of the sleep abnormalities found in depression also persist in remission, suggesting that these parameters could represent trait or vulnerability markers. In a previous study, we found that about one third of a group of high-risk probands (HRPs) showed sleep patterns that were comparable to those of depressed patients. In the present study, we re-investigated a subsample of these HRPs to evaluate the stability of these findings over time. METHODS: We investigated the sleep-electroencephalograms of 82 healthy subjects with a high genetic load of affective disorders. We were able to re-investigate 26 of these HRPs after a mean interval of 3.5 years. Thirty-five unrelated control probands and 33 unrelated depressed inpatients that were recruited at the first investigation served as reference groups. RESULTS: At index investigation, we found that the HRPs showed a significantly increased rapid eye movement (REM) sleep density compared to control subjects. At the second examination, no changes of the polysomnographic observations over time could be observed; in particular, the REM density remained elevated. CONCLUSIONS: The increased REM density in high-risk subjects for an affective disorder at index investigation was stable over time, so that one of the requirements for a true vulnerability marker is fulfilled.     

Premorbid performance IQ deficit in schizophrenia

OBJECTIVE: Performance IQ (PIQ) is often lower than verbal IQ (VIQ) in schizophrenic patients. Whether PIQ < VIQ precedes psychotic symptoms in schizophrenia remains uncertain. METHOD: We investigated premorbid IQ scores in 63 subjects assessed at a child and adolescent psychiatric unit (mean age 13.1 years, SD 3.2), who at follow-up in adulthood (mean age 30.9 years, SD 3.9) received a lifetime RDC diagnosis of schizophrenia-related psychosis, affective disorder, or no psychiatric disorder. RESULTS: Premorbid PIQ < VIQ significantly differentiated the groups with schizophrenia-related psychosis and no psychiatric disorder. Subjects with schizophrenia-related psychosis had a significantly lower mean value for premorbid PIQ, but not VIQ, compared to subjects who developed affective disorder or subjects without psychiatric disorder. CONCLUSION: Our results emphasize premorbid intellectual deficits in schizophrenia. Those deficits might largely be in consequence of an impairment on the PIQ scale.     

Sleep electroencephalographic coherence abnormalities in individuals at high risk for depression: a pilot study.

BACKGROUND: Sleep electroencephalographic (EEG) studies of individuals with major depressive disorder have identified several microarchitectural features associated with the illness. These abnormalities are also found in clinically remitted individuals, raising the question of whether they are vulnerability markers of depression. This study evaluated the sleep EEG in high-risk individuals to see if abnormalities are present in the sleep EEG prior to the onset of illness. METHODS: A total of 26 subjects (13 males and 13 females) were recruited for study on the basis of 1) having a parent or grandparent treated for major depressive or bipolar affective disorder and 2) having no history of personal psychiatric illness. Polysomnographic data were collected and compared with gender- and age-matched healthy control subjects with no personal or family history of psychiatric illness. The primary outcome measures were interhemispheric and intrahemispheric coherence. RESULTS: Period analysis of the sleep EEG showed that beta-delta coherence was lower bilaterally in male high-risk subjects. Right-hemispheric theta-delta coherence was also lower in male high-risk subjects, with female high-risk subjects evidencing lower beta coherence. CONCLUSIONS: Sleep-EEG abnormalities associated with major depressive disorder are present in never mentally ill individuals at high risk for the illness. These markers may be useful in the prediction of illness and in family genetic studies of mood disorders.     

Schizophrenics with tardive dyskinesia. Neuropsychological deficit and family psychopathology

We investigated the role neurologic soft signs, premorbid asociality, psychometric tests, and family history of psychiatric illness may play in the identification of patients at risk for tardive dyskinesia (TD) development. Thirty-two TD and 32 non-TD schizophrenics served as subjects. The results indicated that patients with TD have more soft signs, are more frequently rated as poor premorbid asocials, perform more poorly on psychometric testing, and have a familial loading for affective disorders in first-degree relatives higher than control patients. A discriminant function analysis correctly classified 84.4% of the patients into their respective groups. Subtle yet quantifiable differences exist between TD and non-TD patients and these deficits may render the individual more vulnerable to TD development.     

Premorbid childhood ocular alignment abnormalities and adult schizophrenia-spectrum disorder

This study examined the relation between childhood ocular alignment deficits and adult psychiatric outcomes among children at high-risk for schizophrenia and controls. A sample of 265 Danish children was administered a standardized eye exam assessing strabismus and related ocular alignment deficits. All children whose mothers or fathers had a psychiatric diagnosis of schizophrenia comprised the first group (N=90). Children who had at least one parent with a diagnosis other than schizophrenia comprised the first matched control group (N=93). The second control group consisted of children with no parental diagnoses (N=82). In 1992, adult psychiatric outcome data were obtained for 242 of the original subjects. It was found that children who later developed a schizophrenia-spectrum disorder had significantly higher eye exam scale and strabismus scale scores compared to children who developed other non-psychotic psychopathology and children who did not develop a mental illness. The mean rank for children in the high-risk group (offspring of parents with schizophrenia) on the eye scale and the strabismus scale was greater than the mean rank for children in the matched control groups (both offspring of parents with other non-psychotic disorder and no mental illness), although the results failed to reach statistical significance. Results from this study suggest a premorbid relation between ocular deficits and schizophrenia-spectrum disorders in childhood prior to onset of psychopathology in adulthood. Strabismus may serve as a premorbid marker for spectrum disorders and may have implications for the understanding of early aberrant neurological development related to later schizophrenia-spectrum disorders.     

Multivariate analyses of anthropometric and psychometric variables in probands with affective disorders and their families.

Data on 121 subjects, probands with affective disorders, their spouses and first degree relatives, are analyzed by multivariate methods to determine the relationships between physical types and propensity to illness. 56 variables are used: 39 anthropometric measures, age, sex, and 15 psychometric scales. In a canonical analysis between the anthropometric measures and the psychiatric scales, each canonical variable is found to be largely identified with a single psychometric component, as found in a principal components analysis of the psychometric scales. The two major anthropometric components, size and linearity, do not have any clear relationship with the psychometric components. However, a discriminant analysis that takes each individual as being in one of four clinical groups, normal, unipolar depressed, bipolar affective disorder or other, indicates a clear relationship between the anthropometric measures and mental illness; wide face and deep chest are associated with patients who have bipolar affective disorder. Half of the variables studied are sufficient to give virtually the same amount of discrimination as all 56 variables.     

Lifetime diagnoses in patients with somatoform disorders: Which came first?

Thirty inpatients with somatoform disorders were examined with the structured clinical interview SCID for psychiatric lifetime diagnosis. In the present diagnoses, we found a concordance of 63% for somatoform and affective disorders and the lifetime comorbidity of both disorders was 87%. Additionally, patients with somatoform disorders frequently had a history of other psychiatric disorders (for example, anxiety disorders, 40%). For 73% of patients with somatoform disorders and a history of affective disorders, the onset of the somatoform disorder was prior to the onset of another psychiatric disorder. The time interval between the onsets of somatoform disorders and affective disorders was greater than 1 year for most patients; for 46% of the patients with a history of both disorders, the time interval between the two disorders was more than 5 years. The course of illness for somatoform and affective disorders was quite different; while affective disorders tended to episodic periods with interim remissions, the somatoform disorders usually showed long, chronic courses (mean duration of the current somatoform disorder was 11.9 years). Finally, the Symptom Check List SCL-90R demonstrated good discrimination between patients with affective and anxiety disorders. However, the SCL-90R failed to discriminate patients with somatoform disorders from affective- and anxiety-disordered subjects. Therefore, the development of other psychometric scales is necessary for the evaluation of patients with somatoform disorders.     

Do personality traits predict first onset in depressive and bipolar disorder?

The aim was to investigate whether personality traits predict onset of the first depressive or manic episode (the vulnerability hypothesis) and whether personality might be altered by the mood disorder (the scar hypothesis). A systematic review of population-based and high-risk studies concerning personality traits and affective disorder in adults was conducted. Nine cross-sectional high-risk studies, seven longitudinal high-risk studies and nine longitudinal population-based studies were found. Most studies support the vulnerability hypothesis and there is evidence that neuroticism is a premorbid risk factor for developing depressive disorder. The evidence for the scar hypothesis is sparse, but the studies with the strongest design showed evidence for both hypotheses. Only few studies of bipolar disorder were found and the association between personality traits and bipolar disorder is unclear. Neuroticism seem to be a risk factor by which vulnerable individuals can be identified, thus preventing the development of depressive disorder. A connection between personality traits and development of bipolar disorder, and evidence of a personality-changing effect of affective episodes need to be further investigated.     

Premorbid intelligence of inpatients with different psychiatric diagnoses does not differ

The diagnostic specificity of poor premorbid intelligence is controversial. We explored premorbid intelligence level in psychiatric patients with personality disorders, depressive disorders, bipolar disorders and schizophrenic disorders. 273 consecutively admitted patients and 81 controls were included in the study and tested with the ‘Test di Intelligenza Breve’, an Italian adaptation of the National Adult Reading Test. Significant differences between the clinical samples and the control subjects were found but not among the 4 clinical groups. The observation of premorbid IQ deficits in subjects with diagnoses other than schizophrenia suggests a common vulnerability diathesis, which is most likely to have a neurodevelopmental basis.     

Vulnerability before, during, and after a major depressive episode: a 3-wave population-based study

BACKGROUND: Vulnerability as defined by high levels of neuroticism, low self-esteem, and poor coping skills characterizes individuals with a history of major depressive episodes (MDEs). OBJECTIVE: To separate postmorbid vulnerability into (1) trait effects (ie, the continuation of premorbid vulnerability); (2) state effects of subthreshold (residual) symptoms on personality or its perception; and/or (3) scar effects (ie, negative personality change that develops during an MDE and persists beyond MDE remission). METHODS: Data come from the Netherlands Mental Health Survey and Incidence Study, a prospective Dutch psychiatric population-based survey. We obtained psychiatric (Composite International Diagnostic Interview) and personality data on neuroticism, depressive coping style, self-esteem, and mastery from 4796 respondents at 3 time points (T1, T2, and T3), 12 and 24 months apart. Between- and within-subjects differences were tested with repeated-measures analysis of variance and adjusted for sex, age, and time. RESULTS: After T1, 409 respondents developed an MDE, of whom 334 were MDE-free at T3. In comparison with individuals without any lifetime MDE, the 262 subjects with a first MDE had higher premorbid T1 vulnerability scores on each personality measure (0.38-0.83 effect size units). During the MDE, vulnerability scores further increased (0.33-0.52 effect size units) but returned to premorbid levels after MDE remission. We found no scar effects among subgroups with severe or long-lasting MDEs. Subthreshold residual symptoms at T3 biased comparisons between T1 and T3 if the premorbid period of T1 to MDE onset was longer than the postmorbid period of MDE remission to T3, misleadingly suggesting scar effects. We obtained similar results in the 147 subjects with recurrent MDEs. CONCLUSIONS: There was no evidence of a negative change from premorbid to postmorbid assessment for any of the personality traits. Postmorbid vulnerability reflected the continuation of premorbid vulnerability. Pre-post MDE comparisons are sensitive to prodromal and residual symptoms. Our findings suggest 2 independent simultaneous processes: (1) the ongoing expression of vulnerability as a personality deviance; and (2) synchrony of change between severity of depressive symptoms and personality deviance.     

Premorbid abnormalities in mania,schizomania, acute schizophrenia and chronic schizophrenia

The aim of this study was to examine the hypothesis that differences in outcome among affective and non-affective psychoses are associated with differences in the degree of developmental deviance. We conducted a retrospective survey of first contact cases treated over a 20-year period in a psychiatric hospital serving a catchment area in South London. All patients with non-depressive functional psychoses residing in the catchment area who received their first psychiatric treatment between 1965 and 1984 were included in the study. Cases were classified according to the relative chronicity of their illness into four non-overlapping groups: mania, schizomania, acute schizophrenia and chronic schizophrenia. There was a linear trend in the association between illness chronicity and proxy measures of developmental deviance, such as premorbid unemployment, single status and poor academic achievement. Compared to individuals with mania, schizophrenic patients had a 3–6 times increased risk of premorbid abnormality. For patients with schizomania and acute schizophrenia, the risk was 1.5–3 times greater than for manic subjects. We conclude that the prevalence of premorbid abnormalities is highest among chronic schizophrenia, but similar disturbances also occur, to a lesser degree, in less disabling affective and non-affective psychotic disorders.MRC Social Psychiatry Unit, Institute of Psychiatry     

Subclinical psychopathology and socio-economic status in unaffected twins discordant for affective disorder

BACKGROUND: The most potent risk factor for affective disorders is a family history of affective disorder but the specific factors that are transmitted in families are unknown. It is possible to investigate the relation between risk factors and affective disorder by using a high-risk design e.g.: a study of the healthy relatives of patients with affective disorders. AIM: To compare psychopathology and socio-economic status between twins with a co-twin history of affective disorder and twins without. METHODS: In a cross-sectional high-risk case-control study, healthy monozygotic and dizygotic twins with (High-Risk twins) and without (Low-Risk twins) a co-twin history of affective disorder were identified through nation-wide registers. Participants were assessed using semi-structured psychiatric interviews and self-rating of psychopathology. RESULTS: High-Risk twins had a lower education level, a lower work position and tendency towards being more often unemployed and early retired than the Low-Risk twins. Furthermore, they presented higher rates of subclinical affective symptoms and were more likely to experience a minor psychiatric diagnosis. CONCLUSION: Healthy twins with a high genetic liability to affective disorder seem to present lower socio-economic status, higher rates of subclinical affective symptoms and more often experience a minor psychiatric diagnosis than twins with no familial history of affective disorder. It is not possible from the present cross-sectional data to determine the causality of these findings, thus genetic liability to affective disorder, socio-economic status and minor psychopathology seem to have a complex interrelation.     

Suicide among older psychiatric inpatients: an evidence-based study of a high-risk group.

OBJECTIVE: Older adults have elevated suicide rates, especially in the presence of a psychiatric disorder, yet not much is known about predictors for suicide within this high-risk group. The current study examines the characteristics associated with suicide among older adults who are admitted to a psychiatric hospital. METHOD: All persons aged 60 and older living in Denmark who were hospitalized with psychiatric disorders during 1990-2000 were included in the study. Using a case-control design and logistic regression analysis, the authors calculated the suicide risk associated with specific patient characteristics. RESULTS: Affective disorders were found to be associated with an almost twofold higher risk of suicide among psychiatric inpatients than other types of disorders (95% confidence interval [CI]: 1.5-2.6). Patients with dementia had a significantly lower risk ratio of 0.2 (95% CI: 0.1-0.3). In combination with other types of disorder, affective disorders were found to modify an increased risk of suicide. First versus later admission for depression was a better predictor for suicide than age at first hospitalization for depression (before or after age 60 years). More than half of suicides occurred either within the first week of admission or discharge (chi(2) [1] = 27.70, p <0.001) compared with the distribution of patient days. CONCLUSIONS: Our findings underline the important role of affective disorder in combination with other types of disorders. Assessment of suicide risk among older psychiatric inpatients should take current or previous episodes of affective illness into consideration and pay special heed to the time shortly after admission and discharge.     

Multiple diagnoses in posttraumatic stress disorder in the victims of a natural disaster.

A population of the fire fighters who had been exposed to a natural disaster were screened using the General Health Questionnaire 4, 11, and 29 months after a natural disaster. On the basis of these data, a high-risk group of subjects who had scored as cases and probable cases and a symptom-free comparison group were interviewed using the Diagnostic Interview Schedule 42 months after the disaster. The prevalence of posttraumatic stress disorder (PTSD), affective disorders, and anxiety disorders was examined. Only 23% of the 70 subjects who had developed a PTSD did not attract a further diagnosis, with major depression being the most common concurrent disorder. Comorbidity appeared to be an important predictor of chronic PTSD, especially with panic disorder and phobic disorders. The subjects who had only a PTSD appeared to have had the highest exposure to the disaster. Adversity experienced both before and after the disaster influenced the onset of both anxiety and affective disorders.     

Sleep disorders and child and adolescent psychiatric illnesses

As a symptom of many psychiatric disorders of childhood and adolescence, sleep disturbances often complicate the course and treatment of the underlying disorder. A somatic aetiology, e.g., as in Kleine-Levin syndrome or narcolepsy, may lead to diagnostic misinterpretations. It is not clear whether specific alterations of sleep architecture already exist in this age group and are thus trait markers for psychiatric disorders. Although it is well-known that sleep problems in adults, especially insomnia, are important in the later development of depressive syndromes, it is not clear whether persistent sleep problems during childhood constitute markers of vulnerability for psychiatric disorders. This review demonstrates interactions between sleep disturbances and psychiatric disorders of childhood and adolescence and their importance for assessment and therapy.     

Psychopathology among offspring of parents with schizophrenia: relationship to premorbid impairments

INTRODUCTION: A broad range of psychopathology, including externalizing disorders is seen in offspring at genetic risk for schizophrenia. However, it is unclear whether such psychopathology may underlie a higher predisposition to the premorbid antecedents of schizophrenia. We examined the prevalence and correlates of psychopathology in an ongoing study of offspring genetically at risk for schizophrenia. METHODS: Seventy five consenting high risk offspring (HR: offspring, age 15.68+/-3.27 years; male/female 34/41) and 82 matched comparison subjects (40 males and 42 females; age 15.92+/-3.0 years) participated in this study. Diagnoses were ascertained using structured psychiatric interviews and consensus meetings, including all available clinical information. RESULTS: Sixty (60%) of the HR offspring had one or more lifetime diagnosis of axis I psychiatric disorder. HR subjects with axis I psychopathology had significantly more soft neurological signs, poorer premorbid adjustment, and higher schizotypy scores as measured by Chapman psychosis proneness scales. Among those with psychopathology, HR subjects with externalizing disorders showed the most abnormal scores in schizotypy. DISCUSSION: A substantial proportion of HR offspring of parents with schizophrenia manifest a broad range of childhood psychiatric disorders. Psychopathology, especially externalizing disorders such as attention deficit hyperactivity disorder (ADHD) may represent a subgroup with an increased risk for schizophrenia spectrum disorders. This possibility needs to be examined by prospective follow-up studies, and would be of considerable importance to early diagnosis and intervention efforts in schizophrenia.