Does schizophrenia somehow damage genetics

Psychosis, early detection

Early signs and possible interventions in psychotic developments

A lecture at the Hannover Medical School on the occasion of the conference "Schizophrenia Early Intervention and Long-Term Support"

The scientific study of childhood psychoses does not have a very long tradition. Only from the middle of the 19th century was there isolated references to the occurrence of child psychoses.

These descriptions, however, were not yet about psychoses as we understand them today and diagnosing them with modern classification schemes, but about diseases that are both etiologically and symptomatologically very different, for example GÜNTZ (1859) spoke of so-called "overburdening psychoses" of childhood By which he understood psychological decompensation images as a result of school "overburdening", today we would say the consequence of "school stress". It was not until the middle of the last century that various child psychiatrists defined the clinical picture of "child schizophrenia" more closely. First and foremost, the two Swiss child and youth psychiatrists Jakob LUTZ and Moritz TRAMER should be mentioned here. In the meantime, careful clinical-phenomenological and course typological investigations have proven the existence of childhood schizophrenia. Among other things, through our own long-term studies and through the use of modern classification systems (ICD-10, DSM-IV), the nosological connection between schizophrenic psychoses in childhood and adulthood could be proven (EGGERS and BUNK 1997, 1999). However, childhood schizophrenia is rare. The prevalence before the age of 15 is 1.4 per 100,000 (McKENNA et al. 1994). In adolescence there is a significant increase in the rate of manifestation with a peak between the ages of 16 and 30 (McCLELLAN and WERRY 2001).
The main age at risk of a schizophrenic illness is thus in adolescence and young adulthood. Around 77% of all cases of illness occur before the age of 30 (HÄFNER & AN DER HEIDEN 2000).

In the last few decades, monitoring the course of schizophrenic psychoses of all ages has played a central role. It is astonishing that there are only very few long-term courses with sufficiently long observation times in the literature.

In their meta-analysis of a total of 320 follow-up examinations of schizophrenic psychoses in adults, HERGARTY et al. (1994) only in 5.7% courses with an average observation time of? 20 years, 57% of the courses only had a follow-up period of <5 years.

Most recently, interest has turned to the early stages of schizophrenic psychosis. In particular, it concerns questions of early detection and treatment. Early detection of schizophrenia is difficult. On the one hand, the individually very variable and above all unspecific symptoms in the early phase of the disease make it difficult to identify the symptoms as harbingers or prodromal symptoms of schizophrenia (ADAM & LEHMKUHL 2002). This is particularly true for schizophrenic psychoses in childhood and adolescence. A diagnostic problem here is the development-dependent manifestation of schizophrenic symptoms, because the disease begins in very different phases of development and the symptoms show a corresponding age-dependent color.

In the run-up to a schizophrenic psychosis, different phases must be distinguished from one another:

  • the premorbid development
  • the prodromal stage and
  • the psychotic preliminary phase.

1. Premorbid development

The term "premorbid" is ambiguous. It relates to characteristics and behavioral problems of a patient that are already manifest before a clear psychotic episode. In the classic schizophrenia literature, the term "premorbid character" was used, a term that is unsuitable for children and adolescents, as their personality development is still in full swing. In addition, behavioral abnormalities that can be observed premorbidly can merge into prodromes or be difficult to distinguish from them (PERKINS et al. 2000, YUNG et al. 1996). For these reasons we use the term "premorbid development".

Above all, Anglo-American authors include children with a very early onset of the disease in their studies, in some cases the age of onset is early on in infancy! In this respect, it is not surprising that these authors describe premorbid symptoms of a profound developmental disorder (PDD = Pervasive Developmental Disorder), such as symptoms of Kanner's early childhood autism, severe disorders of psychomotor and linguistic development, lack of social responsiveness (ALAGHBAND-RAD et al. 1995, ASARNOW 1999, WALKER et al. 1999). In our opinion, schizophrenia cannot be diagnosed with sufficient certainty before the age of 7. On the other hand, psychotiform syndromes that manifest earlier are to be assigned to the "childhood psychoses which cannot be classified in any more detail", which are nosologically differentiated from real early schizophrenia.

We briefly report on premorbid abnormalities in "core cases" of childhood schizophrenia from our long-term history that have been confirmed by the catamnestically and are diagnostically narrowly delimited. The premorbid development of children with an early onset of the disease can be recorded easily because the parents can report on it promptly. The patients examined by us had correspondingly detailed, plastic and comprehensive descriptions in the medical files. The age of onset was between 7 and 14 years. The sample of the first follow-up study with an average follow-up period of 15 years comprises 57 patients (31 = female, 26 = male). In 26 of them (45.5%) we found no premorbid abnormalities, the children were rated as sociable, happy, balanced, emotionally vibrating, loving, affectionate, hardworking, fun-loving, sporty, without neurotic tendencies and as good or average students with age-related interests and Hobbies described. On the other hand, 31 patients (54.5%) already showed premorbid traits and behaviors that indicated disturbances in the contact area, in adaptive behavior and in assertiveness. It was about poor out-of-contact loners, overly sensitive, slightly offended children with a tendency to "over-sensitivity", who withdrew themselves seriously, quietly brooding, were often not very affectionate and affectionate, rejected tenderness, sometimes also very self-centered and stubborn or solitary- were strange and anxious (see Table 1). Similar premorbid abnormalities were also reported by ALAGHBAND-RAD (1995), HOLLIS (1995), MAZIADE et al. (1996) and MCCLELLAN & MCCURRY (1999).

As in adult studies, we found a positive relationship between good premorbid adaptation and degree of remission in the first sample; premorbid unremarkable children had a much better chance of recovery than premorbid children.

In our second follow-up study on a remaining group of 44 of the originally 57 patients (follow-up period: 42 years) we used the modified rating scale to assess the premorbid development (M-PAS). There is a connection between creeping onset, early age of onset and premorbid abnormalities, assessed by the M-PAS.

Children with onset of psychosis before the age of 12 tend to have a creeping start type and are more noticeable in terms of premorbidity than children who become ill or psychotic after the age of 12.

The M-Pas comprises 3 subscales, which cover the following areas: contact behavior (good contact skills versus withdrawal), peer relationships and interests

Since we consider the M-PAS to be an inadequate diagnostic inventory for assessing premorbid abnormalities in schizophrenic psychoses, we have developed our own scale for assessing premorbid psychopathological abnormalities (EGGERS et al. 2000). It is a 10-point scale.

Most of the premorbid abnormalities listed in Table 3 are not covered by the M-PAS. They have been observed in our patients between the ages of 3 and 10 years. The symptoms listed were grouped into 10 categories: loss of interest, depressive mood, shyness, paranoia, fears, suicidality, bizarre behavior, aggression, isolation and obsession.

Based on the scale we developed for assessing the premorbid development of schizophrenic children (Premorbid Symptom Checklist, PSCL), we came to a similar assessment of the premorbid development in all 44 patients of the 2nd follow-up examination as in the 1st follow-up examination: 41% were premorbid inconspicuous , 59%, on the other hand, showed abnormalities in their emotional and social development (BUNK et al. 2003). The second follow-up also showed a positive correlation (r = 38, p <0.05) between premorbid social withdrawal behavior with shyness and introversion on the one hand and poor social adaptation on the other, rated by the Mannheim version of the Disability Adaption Scale (M DAS).

In order to reduce the extensive 10-category system and to summarize it again, a varimax rotated factor analysis was calculated. This resulted in four factors that explain 75.3% of the total variance. Charges <.40 were omitted. As described in Table 4, the 10 items can be grouped into four categories:

  1. Emotional withdrawal and sensitivity (EWS). This factor includes the items loss of interest, depression, shyness, suicidality and compulsions.
  2. Existential fears (ED). This factor includes the items paranoia, fear and suicidality.
  3. Overt social maladjustment and hostility (SMH). This factor comprises the items bizarre behavior and aggression.
  4. Avoidant social behavior (SAB), related items are isolation and compulsions.

Based on the PSCL, there were also connections between premorbid abnormalities and age of onset on the one hand and type of starter on the other. Children with an onset age earlier than 12 years and with a gradual onset showed significantly more emotional withdrawal behavior, depression, introversion and existential fears.

It was examined whether there is a connection between the three items of the M PAS and psychopathological symptoms, especially positive, negative and / or global PANSS symptoms at the onset of the disease. There was only a significantly positive correlation between the item "withdrawn" and negative PANSS symptoms (see Table 5). From this it can be concluded that premorbidly withdrawn, introverted children show negative symptoms at the beginning of the psychosis. Hollis (2003) also found a connection between premorbid abnormalities (high PAS values) and negative symptoms in 61 childhood and adolescent schizophrenias.

Furthermore, questions were asked about a possible connection between M PAS items and the relative duration of psychotic episodes with different DSM IV diagnoses. For this purpose, correlations between the M PAS scales and the relative duration of various diagnoses in the course of the disease (longitudinal section) were calculated. There were statistical relationships between the 3 M PAS items and the M-PAS total score on the one hand and the relative duration of the episodes or conditions diagnosed as schizophrenia according to DSM IV 295.XX. This means that children with premorbid problems have longer periods of time in which they suffer from schizophrenic psychosis. As can be seen from Table 6, there are negative correlations between the relative duration of remission states and the M PAS scores, that is, the more pronounced premorbid abnormalities, the less favorable the course or the overall prognosis.

2. Precursor symptoms

Precursor symptoms are referred to as prodromes (prodromos, Greek = precursors). They are to be distinguished from the described premorbid abnormalities as relatively punched out behavior deviations preceding the psychosis. However, this works best with acutely recurring psychoses and relatively poorly with insidious, progressive forms of psychosis. Prodromes differ from premorbid, emotional and behavioral abnormalities v. a. through the intensity of the spectrum of symptoms, which ultimately clearly assumes a psychotic character.

Prodromal symptoms are relatively unspecific phenomena. Psychopathologically, they are mainly characterized by negative symptoms, such as social withdrawal, loss of interest, adynamia, shy inhibition, neglect of physical hygiene, bizarre trains of thought and ridiculous behaviors, insomnia and loss of appetite, declining school performance, unusual distrust and even relationship ideas ("He looks at me so strange "," He wants something for me "," Everyone has conspired against me "). Thought constrictions occur, the patients keep coming back" over the same point ", the thoughts revolve around the same content, stay on "Beginning of a groove". The own person and the environment are experienced as changed, everything has something "meaning". Unmotivated aggressiveness with outbursts of anger and anger and, in adolescence, substance abuse can occur and possibly lead to a misdiagnosis.

In the original sample of the first follow-up examination, 31 of the 57 patients (55%) had prodromes prior to their psychosis. They usually lasted no longer than one to two weeks, very occasionally up to 8 weeks and only once for a year. For the most part, they were one-off and continuously passed into psychosis. It was about short-lasting delusional-depressive or manifest disaffected states, on the one hand a hallucinatory experience with optical hallucinations and anxious-delusional excitement.

The phenomenology of the prodromes was quite diverse. The most common symptoms in the 31 children are listed in Table 7.

Prodromal symptoms largely correspond to the uncharacteristic basic symptoms described by HUBER (2002). Premorbid behavioral deviations, prodromal symptoms and attenuated psychotic symptoms can merge into one another (PERKINS et al. 2000). The prodromal phenomena can either flow continuously into the acute psychotic episode or precede the acute phase for days, weeks or even months. Prodromes can precede the psychosis as so-called outpost syndromes in the form of independent, temporally limited psychopathological status pictures at a time interval of up to several years. We were able to observe this in 3 of 11 children with onset of psychosis before the age of 11, the outpost syndromes appeared at the age of 6, 7 and 8 years and lasted for a few weeks to months. The interval to the first psychotic episode in these children was between 3 and 8 years (EGGERS et al. 2000).

In the cross-sectional view, the adequate assessment and correct classification of prodromal symptoms in children and adolescents is extremely difficult, a difficulty that must not be underestimated! The clear assignment of unusual behavior and abnormalities as prodromal symptoms is ultimately only possible retrospectively, namely after the manifestation of clear psychotic symptoms! After all, in the Mannheim ABC study with the IRAOS, an instrument for retrospectively recording the early course of the psychosis, prodromal symptoms were detected in 4% of the patients examined before the age of 10 (HÄFNER et al. 2002).

The difficulty of diagnosing the onset of schizophrenic psychosis is also evident in the usually long periods of time with a wide variety of psychiatric diagnoses and treatment attempts in advance of the correct diagnosis of schizophrenic diseases. SCHAEFFER and ROSS (2002) prove this very impressively in their empirical study on the medical histories of patients suffering from early schizophrenia. Prior to the final diagnosis, the 17 children whose medical histories were analyzed received 43 different diagnoses such as developmental delay, ADHD, bipolar and depressive disorder, obsessive-compulsive disorder, generalized anxiety disorder, and conduct disorder. A wide range of psychotropic drugs were used, including stimulants, antidepressants, lithium, clonidine, and neuroleptics. Six of the 17 patients, i.e. more than a third, were treated exclusively with massages, chamomile baths or with herbal remedies. In agreement with the findings of other authors (cf. LARSEN et al. 2001), an average of 2 years elapsed between the appearance of the first psychotic symptoms and the correct diagnosis and treatment of the disorder. The patients had their first contact with a doctor / psychologist an average of 2.5 years before the onset of the acute psychotic symptoms. An earlier identification of high-risk patients would have been possible in many cases.

3. Diagnostic procedure

Diagnostic procedure for assessing the early course of psychoses

The most elegant and meaningful procedure for recording early symptoms are prospective longitudinal studies. However, they are associated with difficulties: You need “staying power”. It is best to start from a certain basic population at a defined point in time. The most sensible are birth cohorts from a certain period of time, which then at regular intervals from birth to the target point in time if possible by the same researchers (e.g. CANNON et al. 2002).

In two recent prospective longitudinal studies in which (child) psychiatric follow-up examinations were carried out at regular intervals into adulthood (CANNON et al. 2002, POULTON et al. 2000), the following predictors of psychosis in adulthood were found:

  • unusual distrust
  • High sensitivity
  • Social withdrawal behavior and
  • Self-reports about absurd ideas and
    Childhood perceptions

In a large, four-decade British cohort study of 5,362 individuals born between March 3 and 9, 1946, JONES et al. (1994) collected prospective data at 11 measurement times each up to the age of 16 years. In children who developed schizophrenia later, sometimes not until adulthood, the authors were able to determine the following abnormalities in different child development phases:

  • a delayed motor and language development,
  • a tendency towards withdrawal and loneliness between the ages of four and six
  • social insecurity at age 13 and
  • poor school performance compared to age group.

At the age of 15, the children who later developed schizophrenia were classified by teachers as conspicuously anxious. At the ages of 8, 11, and 15, these children had lower IQ scores than the age norm.

DONE et al. (1994) in a cohort study of 7-11 year old children who later developed schizophrenia. The results of the Finnish cohort study support these findings (review by ISOHANNI et al. 2000). DONE et al. (1994) also found gender differences: boys showed an overreactive acting-out behavior at the age of eleven, while girls at this age tended to show the opposite pattern of social mismatches; they were reserved, less communicative, inhibited and socially withdrawn.

In summary, psychosocial and emotional behavioral deviations on the one hand and cognitive impairments on the other can be determined in the history of patients who became ill in adulthood. The latter are partly associated with linguistic, perceptual and motor development disorders.

4. Early warning signs

In the more recent research on precursor symptoms of schizophrenic psychoses in adulthood, a distinction is made between so-called "psychosis-remote" and "psychosis-related" prodromes. By precursor symptoms close to psychosis one understands weakened psychotic symptoms such as paranoid ideas, extreme mistrust, relationship ideas that are very similar to the psychotic symptoms and are in a direct temporal connection with the full onset of the psychosis.

We were able to observe such psychosis-related prodromes in 23 test subjects (52.3%) of the sample of our second follow-up investigation (n = 44); the distribution is shown in Table 8.

In recent times, the research interest has centered on the question of whether so-called early warning signs can be identified as long as possible before the actual onset of the psychosis, the timely diagnosis of which could lead to a shortening of the interval preceding the psychosis. By shortening the untreated period (= DUP, Duration of Untreated Psychosis) one hopes to improve the overall prognosis. In our sample of 44 patients examined for the second time with an average total observation period of 42 years, it was shown that the interval between the age at the first appearance of unspecific psychiatric symptoms and the time with clearly psychotic symptoms was longer than the interval between the occurrence more clearly psychotic symptoms and initial hospitalization (1.4 years versus 4 months). In the adolescent psychoses (n = 44) the situation was reversed (see Table 9).

Whether the modern imaging methods in the area of ​​brain structural aberrations can also be used for early detection depends crucially on the question of whether such abnormalities are the cause or consequence of the disease. According to the current state of knowledge, it can be assumed that the brain anomalies predominantly arose before the onset of the disease and that they remain stable over the course of the disease. Such anomalies may be related to early brain damage or neuronal development disorders, as pregnancy and childbirth complications as well as early childhood brain diseases often occur in the previous history of those affected. Only a small group of sufferers shows slow progression of the brain changes (KUMRA et al. 2000). It is not yet possible to determine with certainty whether this is an independent subgroup.
In order to make practical use of the area of ​​structural brain aberrations for early detection, the extent to which discrete deviations from the norm in imaging findings can be viewed as specific indicators of later schizophrenic psychosis compared with healthy people must first be investigated. If people who become ill later differ from healthy people at an early stage, this could lead to an improvement in early detection.

The structural changes in the brain structure mentioned are partly due to prenatal migration disorders of neuronal cells in subcortical and cortical structures. Hereditary influences as well as pre- and perinatal oxygen deficiencies are held responsible for this.


5. Early intervention

A major problem is the specification of so-called early symptoms and early warning signs before the onset of a psychosis. They are to be regarded as unspecific, especially for children and adolescents. The low specificity and only moderate prognostic valence of risk conditions and early warning signs in no way allow a responsible statement to be made about the probability of a psychotic illness in individual cases.

MALLA and NORMAN (2002) and WARNER (2001) also come to the conclusion in their critical assessment of corresponding studies that, due to the unspecificity of the symptoms in the prodromal period, the risk of false positive results is relatively high.

In addition, early therapeutic interventions can lead to the occurrence of very undesirable side effects, so that the decision on early treatment must be made extremely critically and cautiously. The benefit and risk of treatment should be weighed carefully. Ethical aspects must also be taken into account, such as premature alarm and stigmatization of the patient and his relatives!

So far there is no convincing controlled study that would prove the effectiveness of early interventions in schizophrenic psychosis! This is also the result of LARSEN et al. (2001). The authors subject several early detection and early intervention studies to a critical meta-analytical evaluation and each come to the conclusion that there are no clear, methodologically clean and convincing studies that clearly prove the sense and benefit of early intervention! MALLA and NORMAN (2002) also come to similar conclusions.

Contrary to the general euphoria with regard to the early detection of schizophrenic psychoses, extreme caution and restraint are required, especially with children whose behavioral repertoire is to be regarded as pluripotent. Children who show prodromal unspecific behavioral abnormalities described at the beginning only very rarely develop a psychotic illness, and it would be devastating to consider all of these children as potentially psychotic and subject them to a screening process! So far, one has moved between Scylla and Charybdis: between possible but uncertain benefit and unnecessary and unjustified uncertainty of young patients and their relatives. Especially in puberty, early and late adolescence, uncertainties about growing into the adult role, excessive demands due to unresolved autonomy and detachment conflicts, uncertainties in psycho-sexual identity and difficulties in "shedding children's shoes" represent age-typical problems that are too unspecific on the behavioral level Irritations such as strong self-doubt, social withdrawal, contact difficulties, social fears, performance failure, all symptoms that can also occur in the run-up to schizophrenic psychoses. Careful and tactful observation of such children is sensible, but not therapeutic snap-shots, especially not with side effects Psychopharmaceuticals! It should be noted in particular that we know next to nothing about the long-term effects of both typical and atypical neuroleptics on the developing brains of children and adolescents.

Despite these restrictions, however, it is advisable to identify risk groups as early as possible and to examine them at regular intervals and, if necessary, to treat them according to the so-called psycho-educational model (family crisis management, stress management, improvement of coping strategies, early detection of early warning signs, etc.) . This preventive model largely corresponds to the program of post-inpatient further treatment of schizophrenic patients with the aim of relapse prevention and careful reintegration into everyday life.

6. Prevention

One of the most important findings of the prospective study by JONES et al. (1994) was that the mothers of the later schizophrenic sufferers showed significantly reduced maternal skills and were impaired in their understanding of their child. They were found to have a reduced capacity for empathy and inadequate parenting behavior. The lack of supportive intimate relationships strongly correlated with the chronicity of the child disorder. Breaks in family life, in social relationships and in the professional activities of parents of schizophrenic and depressed children have also been described. Just like JONES et al. (1994) CANNON et al. (2002) and MYHRMAN et al. (1996) later described interaction disorders between mother and child in the history of adult subjects suffering from schizophrenia.

It can be concluded from these findings that promoting parental and interactive skills makes sense. Children growing up in secure and stable relationships have greater opportunities to develop into self-confident and autonomous personalities, as the results of attachment research have impressively demonstrated (for details see ZIEGENHAIN 2003). Evaluation studies have shown that careful advice at an early stage can improve parental sensitivity and strengthen the interactive skills of young parents. The studies by RAINE et al. (2003) were able to show that a preventive early intervention program in early childhood can have a preventive effect on the development of schizotypical personality traits between the ages of 17 and 23, among other things. These general preventive measures are of course only of low specificity, however sensible they are for the individual development chances of the child.

7. Conclusion

Together with JONES and TARRANT (1998, 1999), we are of the opinion that the lack of specificity of precursor symptoms and developmental deviations and the overlap with other disease risks "still do not allow a practicable early detection of a future disease on an individual level". ISOHANNI et al. (2000), based on their prospective long-term study on a birth cohort of a total of 12,058 live births, come to the conclusion that none of the premorbid symptoms and risk factors described by them have proven to be specific for the later development of schizophrenic psychosis and would be somehow appropriate to reduce the risk for a Predict schizophrenia in the general population.

Children who change their behavior significantly without sufficient reason should, however, be presented to the child and adolescent psychiatrist, following the motto: "Better once too much than once too little" , severe anxiety, unusual suspiciousness, abnormal thoughts, pronounced concentration and attention disorders and inexplicable, groundless aggressive behavior, the affected person should be examined and looked after particularly carefully, regularly and carefully, without prematurely stigmatizing and worrying.

A graphic, model overview of risk factors, early symptoms, prevention and therapy is shown in Fig. 4.