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Vulnerability and Resilience

The Burden of Incomplete Treatments

Little is known about the etiology of major psychiatric disorders, and a diagnostic differentiation based on biological markers or objective laboratory methods is currently not available. Accordingly, it is hardly surprising that only incomplete treatments for these disorders are in use and that there is no cure in the majority of cases. Pharmacological treatment, though effective, is unsatisfactory in the sense that (1) a large proportion of patients (35% - 45%) exhibit a refractory clinical picture which is resistant to all treatment modalities, and (2) the question of predicting treatment response in the individual patient is not answerable for any of the currently available antipsychotics and antidepressants.

Etiology of Major Psychiatric Disorders

Evidence from twin, family and adoption studies suggests that, ultimately, genetic markers may represent the most important trait-like characteristics in the etiology of major psychiatric disorders. However, genetic predisposition appears to vary across patients and to "explain" no more than 25% to 60% of the observed phenotypic variance, depending on the onset of illness, severity of illness, and long-term course of clinical syndromes. Therefore, genetic predisposition has been conceptualized as acting nonspecifically, by elevating a subject's "vulnerability" (or "sensitivity") to environmental or endogenous challenges. Vulnerability, however, is neither necessary nor sufficient for the development of psychiatric disorders.

Mechanisms that Support and Maintain Health

A subject's vulnerability is typically compensated, at least in part, by resilience factors. The term "resilience" is used here as a broader concept than just neurogenesis, encompassing all those intrinsic/endogenous mechanisms that support and maintain health, thereby enabling patients to cope with stressful situations (includes the concept of autotherapeutic capacity). This may include personality traits supporting or impeding social skills.

Molecular-Genetic Evidence

In our molecular-genetic study of 257 patients treated with antidepressants or antipsychotics and genotyped for 178 candidate genes, we found correlations as high as 0.5604 (p = 0.0000; nonimprovers included; c95 = [0.4123, 0.6797]) between the phenotype (onset of improvement) and the subjects’ coordinate on the first eigenvector of a configuration of 26 genomic loci (31% explained phenotypic variance). Positive as well as negative correlations of the same order of magnitude were detected, with the underlying configurations sharing "core" loci while differing in their "accessory" loci, thus suggesting the existence of mechanisms that can support or impede recovery. No single genomic locus seemed to be either necessary or sufficient for having the phenotype, whereas significant non-linear interactions between the genomic loci appeared to play a key role. Interestingly, there was some overlap with genomic regions independently identified as being linked to functional psychoses, again with subgroups displaying positive or negative correlations between the configuration of genomic loci and the phenotype (vulnerability to functional psychoses: affected/unaffected sib pairs).

References

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genetic model
Fig. 10: Genes code for proteins or RNA ("gene products") which may interact among each other and the immediate environment in a variety of ways and influence the phenotype only after a cascade of intermediate steps, that is, genes act quantitatively (examples: receptor affinity, amount of synthesized neurotransmitter, speed of metabolism, modulating factors). As a direct consequence, there is no 1-to-1 mapping between genotype and phenotype but, rather, a so-called "norm of variation".
Please note: even though subjects may exhibit considerable deviations from the "optimal" genetic profiles associated with biological systems (e.g., monoaminergic systems), self-regulation keeps their systems as a whole entity in stable conditions, thus guaranteeing high failure tolerance.
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