Cel de-al XXV-lea Congres SNPCAR

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24-27 septembrie 2025 – Brașov Hotel Kronwell

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Asist. Univ. Dr. Cojocaru Adriana – Președinte SNPCAR


A SYMPTOMS CLUSTER DIMENSIONAL, GENETIC AND NEUROBIOLOGY BASED DIAGNOSTIC APPROACH IN CHILD AND ADOLESCENT PSYCHOTIC DISORDERS: NEW PERSPECTIVES

Autor: Laura Nussbaum Axinia Corcheş Luminiţa Ageu Bianca Micu Șerbu Ghizela Kanalaş
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General context: The existing studies give reasons for not considering schzophrenia as a homogeneous disorder, but one composed of different domains: psychosis, negative symptoms and pathology in interpersonal relations.
Extensive existing literature demonstrates that only the psychotic symptoms are not adequate for predicting outcomes in patients with Schizophrenia.On the contrary, poor rapport, lack of insight, restricted affect, are the most discriminating symptoms in choosing a correct diagnosis.
The four identified dimensions were labelled – depression, reality distorsion, mania and disorganization
The traditional paradigm based on psychosis is inadequate. A new paradigm is needed with basic consequences for the development of new drugs, new therapeutic strategies for non-psychotic dimensions of the disease.
Dimensional rather than categorical constructs seemed to be more helpful for this purposeConclusions and Discussions: The findings from clinical and molecular genetics, brain structural and functional studies and clinical phenomenology are relevant, so that: schizophrenia is a collection of diverse entities, traditional clinical subtypes are mutable over time; We must focus on the characteristic pathological and morphological changes correlated with Schizophrenia risk genes, both alone and in combination, as well as the corresponding footprints of normal variation in the healthy brain.
The objectives of the future researches will be focused on: refining taxonomy of Schizophrenia and other CNS disorders on the basis of molecular markers and using model systems to understand functional biological implications of gene variants.

General Context

The domains of psychopatology provide an alternative paradigm that contemplates schizophrenia as a disorder of several pathological systems.
In this paradigm, the relative independence of: reality distorsion, disorganization, negative symptoms, impaired cognition, is stressed [2].
Psychosis and its correlates are entirely inadequate for characterizing the course of persons with schizophrenia and the impaired cognition and negative symptoms are solidly associated with poor functional outcomes [2].
The existing studies give reasons for not considering schzophrenia as a homogeneous disorder, but one composed of different domains: psychosis, negative simptoms and pathology in interpersonal relations.
Extensive existing literature demonstrates that only the psychotic symptoms are not adequate for predicting outcomes in patients with Schizophrenia.
On the contrary, poor rapport, lack of insight, restricted affect, are the most discriminating symptoms in choosing a correct diagnosis.
Positive psychotic symptoms have low within subjects correlations with negative symptoms and functional outcome measures.
The different component areas of schizophrenia should be addressed as independent domains of pathology and therefore investigated from specific aetiological and therapeutic perspectives.
The traditional paradigm based on psychosis is inadequate. A new paradigm is needed with basic consequences for the development of new drugs, new therapeutic strategies for non-psychotic dimensions of the disease [3].
The pathology paradigm would be better in identifying this pathologies and researching novel drug mechanisms for unmet treatment needs.
The advantages of second generation antipsychotic drugs are real but this does not mean efficacy on cognition.
The aim is to find an antipsychotic medication with high efficacy on cognition.
Future clinical targets for drug discovery involving novel therapeutic pathways are required [3, 10]. Impaired cognition has been wisely identified as the first priority.
The approach of new strategies for the non-psychotic dimension of the disorder is required.
As well, the development of new therapeutic strategies for non-psychotic dimensions of the disease, is compulsory needed.
Recent advances in human genetics have led to an explosion of our understanding of the role that genetic and epigenetic variation plays in determining the susceptibility to a wide range of psychiatric disorders [1].
One of the main challenges to developing next-generation therapeutics for psychiatric disorders is that no common genetic variants of large effect have been identified.
The genetic susceptibility for autism, schizophrenia, bipolar disorder, major depression is polygenic.
The selection of targets for novel drug therapies requires an in-depth understanding of disease biology, from the etiological factors to pathophysiological mechanisms, and their relationship to disease progression and duration.
In concert with functional genomics, high throughput electrophysiology, imaging and integrative systems biology approaches, this perspective platform could provide insights into common and unique mechanisms of syndromic diseases, upon wich new drug discovery paradigms may be founded.
Multimodal models can then be used to identify disease signatures.
Integrative large-scale data provides a path to predict which drug effects might best counteract the molecular networks underlying disease.
Murray V, Miller PM describe the identification and clinical assessment and the distribution of underlying dimensions and classes of the illness in order to characterize the phenotypes of psychosis [5].
The four identified dimensions were labelled – depression, reality distorsion, mania and disorganization:
-class A – depression comprising 19% of the sample
-class B – disorganization comprising 28% of the sample
-class C – bipolar comprising 28% of the sample
-class D – reality distorsion/depression comprising 30% of the sample
These four latent class models provide a useful alternative to classic diagnostic systems.
Peralta V, Cuesta MJ, proposed a polydiagnostic multidimensional paradigm for understanding clinical heterogeneity in schizophrenia, integrating both categorical and dimensional constructs [6].
The authors hypothesized that the various diagnostic systems represent different aspects of the illness and schizophrenia may be at the extreme of the psychotic continuum, which can be extended to nonpsychotic entities such as schizotypal personality.
Evidence shows that the classification of psychosis is not supported on a biological basis.
Overlap of symptoms between bipolar disorder and schizophrenia and related disorders is still to be ascertained and categorical approaches could contribute to obscuring significant finding in genetic research.
The term non-affective psychosis should be reserved for the disorganization class, which represents only a subgroup of Scizophrenia. Each of the other classes has shown an important affective component, wich has been concealed by incorporating heterogeneous cases within the Schizophrenia subgroups.
The clear difference found between the disorganization class and reality distorsion/depression class emphasizes the efficacy of this method in sorting patients with psychosis into clinically significant groups.
These latent classes represent a state rather than a trait and the same patient may fall into one or another of these, depending on when the assessment is performed.
The result of this study will ultimately show their validity only if biological markers are found, differentially distributed across the four classes.
Recent studies contribute to a deeper understanding of the relationships between psychotic and mood disorders (mood disorder with psychotic feature, schizo-affective disorder and Schizophrenia with mood feature) from clinical and pathology perspectives.
Diagnostic stability throught late classification schemes has been poor.
From the perspective of pathology, neuroimaging studies have shown overlapping findings between bipolar disorder and schizophrenia, particularly enlarged ventricles, grey matter volume reductions, or left-less-than-right asymmetry in certain brain areas.
The research for aetiological evidence has resulted in several epidemiological, gene expression, genetic linkage and association studies, where family aggregation of both psychotic and mood symptoms has been consistently found as well as an overlap in specific chromosomal regions that suggests either the existence of psychosis genes.
Overlapping clinical and physiopathological evidence between both disorders signals the importance of future genetic research on specific symptom constellations in order to reach a better understanding of psychosis [4].
Study samples based on features such as psychotic symptoms, cognitive impairment, chronicity or response to treatment may be useful in discerning to what extent genes influence, clinical phenotype or brain region volumetric alterations related to these illnesses.
Dimensional rather than categorical constructs seemed to be more helpful for this purpose [9].
Psychotic bipolar disorder and Schizophrenia show both distinctive and common neuroimaging endophenotypes associated with differential genetic liability, thereby supporting a common neuroanatomical substrate for both disorders with superimposed differential brain alterations in grey matter for each.
Schizophrenia and the psychotic subtype of BPD – Bipolar Disorder share risk genes and pathophysiology differing from non-psychotic BPD.
Because delusions, hallucinations and thought disorder can occur frequently in mood disorder as well as in Schizophrenia the specificity of associated brain changes can be investigated.
Psychotic BPD but not nonpsychotic BPD was associated with some of the structural brain alteration observed in Schizophrenia.
On the contrary, anatomical variations in white matter showed overlapping and generic patterns of volume reduction in the left frontal and tempo-parietal regions for both disorders.
This is a common endophenotypic marker associated with both psychotic disorders.
Biological and epidemiological evidence is given to support the distinction or specificity of new categories such as deficit versus non deficit Schizophrenia or sporadic versus familial Schizophrenia.
Modern epidemiological approaches have also been used to attempt to build a bridge between dimensional and categorical approaches, where a new categorization is put forward as a step towards the investigation of more biological comprehensive diagnostic systems [5].
The course of illness and prediction of outcome in Schizophrenia and Bipolar disorder is best evaluated on a longitudinal rather than a cross sectional basis.
Those disorders are preceeded by developmental deficits that can be detected in infancy and extend through childhood and adolescence to the prodromal periode immediately preceeding the emergence of diagnostic symptoms.
These considerations suggest a model that involves disturbances that disrupt the very earliest stages of brain development and create a compromised nervous system on which variety of endogenous and exogenous physical and psychosocial adversities impact.
That determines the long-term course and outcome within a „lifetime trajectory model of Schizophrenia”, before and after the emergence of diagnostic psychotic symptoms at the first episode: from antecedent childhood abnormalities, through determinants of onset, early cognitive impairment and negative symptoms to progression in structural brain pathology.
There are symptomatic and physiological diferences between familial and sporadic Schizophrenia.
These data allow the subgroups to be thought of, as two different types within Schizophrenia syndrome wich may have implications for stratifying Schizophrenia patients in order to obtain more homogeneous subgroups for research and treatment.
Recent investigations have found clinical and neurobiological difficulties in distinguishing between affective psychoses and nonaffective psychoses [8].
The existent studies dividing Schizophrenia in familial and sporadic subgroups have shown clear promises.
We should take into account the possibility that both groups may have genes conferring vulnerability to the disorder (with different penetrance or different processes of interaction with other variables between the groups).
Cognitive deficits are excellent candidates for endophenotypic markers of familial risk for Schizophrenia because they are present in both patients and unaffected relatives [1, 7].
The high concordance of cognitive dysfunction in individuals with Schizophrenia and their unaffected relatives indicates that expression of shared genetic susceptibility, is more penetrant at the level of cognition than at the level of clinical symptomatology.
Cognitive neuropsychological measures compared to clinical phenomenology are more directly linked to the underlying neuronal systems that are affected by genetic risk factors [1, 7].
Because cognitive deficits make such profound contribution to the persistent functional disabilities of many patient suffering from Schizophrenia, they are becoming recognized as a treatment target for medication (new adjunctive medications) and psychosocial interventions [3, 7, 8, 9].

Conclusions and Discussions

The findings from clinical and molecular genetics, brain structural and functional studies and clinical phenomenology are relevant:
Schizophrenia is a collection of diverse entities
Traditional clinical subtypes are mutable over time
If unaffected frst-degree relatives of Schizophrenia patients carry a proportion of the risk genes, then they should share aspects of both the pathology and the structural brain changes associated with the disorder.
Studies comparing individuals with Schizophrenia with those who suffer from psychotic BPD – Bipolar Disorder and other overlapping syndromes will undoubtedly lead to change in ideas about how to define and subtype psychosis.
We must focus on the characteristic pathological and morphological changes correlated with Schizophrenia risk genes, both alone and in combination, as well as the corresponding footprints of normal variation in the healthy brain.
The objectives of the future researches will be focused on:
Refining taxonomy of Schizophrenia and other CNS – Central Nervous System disorders on the basis of molecular markers.
Using model systems to understand functional biological implications of gene variants

References

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  2. Carpenter Jr WT. Clinical constructs and therapeutic discovery. Schiz Res.2004; 72(1):69-73.
  3. Harvey PD, Rabinowitz J, Eerdekens M, Davidson M. Treatment of cognitive impairment in early psychosis: a comparison of risperidone and haloperidol in a large long-term trial. Am J Psychiatry. 2005; 162:1888-95.
  4. Kempf L, Hussain N, Potash JB. Mood disorder with psychotic features, schizoaffective disorder, and schizophrenia with mood features: trouble at the borders. Int Rev Psychiatry. 2005; 17(1): 9-19.
  5. Murray V, McKee I, Miller PM, et al. Dimensions and classes of psychosis in a population cohort: a four-class, four-dimension model of schizophrenia and affective psychoses.Psychol Med. 2005; 35:499-510.
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