Our purpose ist o approch the theme of modern treatment, early detection and intervention strategies in the mamagement of child and adolescent psychosis, based on the clinical staging model. In the same time we target to analyze the effectiveness of modern pharmacogenetic testing and screening in the clinical setting and practice for an individualized, tailored,personalized path of care and medicine.
We discuss about the clinical implications and future perspectives of different interventional strategies and the quantification in correlation with the CYP2D6 genotype. The clinical staging model help us to evaluate the diagnosis accurately and to apply a proper intervention in an ethical frame.
We intended to bring to the forefront attention the implications of eary intervention and pharmacogenetics for obtaining the optimum efficacy of treatment in the child and adolescent psychosis. A proper eary intervention is of top importance in protecting the child development, so that the timely attention may prevent the course and improve the overall prognosis.
Introduction / Background
In the last 20 years, the emphasis in psychotic disorders was more on identifying, early diagnosis and treatment based on clinical staging model (McGorry & Yung, 2003). The early intervention paradigm is based on the view that, for psychosis, the earliest possible detection and the effective intervention will provide the best outcome for patients and, in time, they will result in lower burdens and costs for the health care system.
During the meta-analyses and the systematic reviews (Perkins et al, 2005), a longer duration of the untreated psychosis (DUP) was associated with a worse response to antipsychotic treatment as measured by the severity of global psychopathology, of positive and negative symptoms and of functional prognosis.
Neuroimaging studies have also indicated that prolonged untreated psychosis is associated with more pronounced structural abnormalities of the brain (Keshavan & Amirsadri, 2007).
The early intervention model presents undeniable evidence of improved functional outcomes both on the short and the long term, of the decrease in the number of hospitalizations (Bertelsen et al, 2008), as well as of economic benefits for the health care system (Killacey and Yung, 2007). Randomized studies have also suggested that the initiation of atypical antipsychotic medication in the first episode of psychosis can prevent the progression of structural brain changes associated with psychotic disorders (Lieberman et al, 2005b, Nakamura et al, 2007).
According to the clinical staging model, when patients are treated early, on time, the risk / benefit dynamics changes and it is important to consider whether a more benign and less extensive treatment, would be sufficient to achieve the same level of remission and recovery or even a higher one.
The clinical staging model of psychosis in children and adolescents is a heuristic framework for the development of more refined forms of diagnosis, for the development and assessment of interventional strategies and for the study of variables and processes underlying the development of psychiatric disorders (McGorry et al, 2008).
Clinical staging differs from conventional diagnostic practice, by its defining the progression of the disorder at a certain point in time and the position where a person is situated in the course of the disease continuum (McGorry et al, 2008).
A staged approach in the choice of treatment within the early stages of the psychotic symptoms could include psychosocial treatments with demonstrated efficacy and without significant side effects and it would avoid the early introduction of antipsychotic medication, assuming the effectiveness of psychosocial treatments at this stage of the disease as proven.
Then, the antipsychotic treatment would be introduced only as second line, when treatments that are more benign have failed or when evidence reveals a more aggressive course of the disorder, within the frame of a staged algorithm of care.
Current studies have proved the efficiency of the staging model as a viable treatment approach in psychoses concerning the pharmacological and psychosocial interventions.
While antipsychotic medication has proven effective in the treatment of acute psychosis, in the first episode of psychosis (Kahn et al, 2008), we must take into account the serious side effects associated with this medication.
The risk analysis indicates the need for a cautious and individualized risk-benefit ratio when prescribing antipsychotics.
Studies have shown that antipsychotics and other drugs (especially lithium, valproate, serotonin reuptake inhibitors, N-acetyl cysteine and Omega 3 fatty acids) would have neuroprotective properties (Amminger, et al, 2009, Berger et al, 2008 Berk et al, 2008a, Lieberman et al, 2005b) and would therefore be important in protecting the patient against the putative “neurotoxic” effects of the subsequent disorder or of the psychosis itself.
The management of psychoses requires a differential and integrative approach to each case, initiated as early as possible in the multidisciplinary team which should act flexibly, coherently, synergistically, in the least restrictive framework while promoting preventive behaviours.
An integrative approach relates to coordination of systems and services, integration of several individual, family, group, and psychosocial interventions leading to the improvement of life quality.
Effectiveness of new psychosocial interventions in early psychosis
Case management. A case manager is assigned to each patient, case management including patient engagement, problem solving, advocacy and support.
Close monitoring and prompt response to the crisis. Patients are given a prompt response from the multidisciplinary team and a tailored, personalized, customized crisis plan, so that assessment and intervention can be provided quickly if necessary.
Cognitive behavioural therapy (CBT). CBT for people with the first psychosis episode / early psychosis focuses on reducing symptoms and stress, on facilitating coping with existing disorder and on the treatment of secondary morbidity such as anxiety, depression and substance abuse. CBT involves the use of strategies for the management of positive psychotic symptoms, such as identification and modification of cognitive styles and of behavioural patterns that may contribute to these symptoms and the promotion of the insight for the existing disease.
Existing studies show that the maximum impact of CBT is in the early stages of psychosis (schizophrenia and bipolar disorder) (Scott et al, 2005; Tarrier, 2005). In addition, the CBT has been proved to contribute to a better adherence to treatment.
Family support and education. The case manager should provide the family with information and psycho-education about psychosis and recovery. Existing researches have shown that family interventions cause and contribute to a decrease in the periods of hospitalization of patients with early psychosis, assisting parents in supporting their sick children in the community.
A family psychosocial module was also an essential component of the intervention in relapse prevention that has proven more effective than standard care in preventing the emergence of a new episode of psychosis (Gleeson et al, 2009). In patients with schizophrenia, the evidence indicates that the relapse rate can be reduced by 20% if family interventions are included in the treatment (Addington & Addington, 2008). The Danish OPUS study also showed that integrated care, consisting of assertive community treatment, multi-family psycho-educational groups and social skills training, resulted in a better outcome for patients with psychotic disorders and for those with disorders in the schizophrenia spectrum as compared to patients who received standard care.
New discoveries in genetics and imaging open opportunities to different classification systems that make the link among symptoms, neuronal circuits and biomarkers. Thus, the diagnosis affects biological research and biological research influences classifications and diagnostic criteria. These inter-disciplinary relationships will help the action on both risk factors and the protective ones, laying the basis of specific interventions.
Research aims at the detection and early intervention by surprising patients in a more responsive phase where impairments are less extensive. Targeted early intervention aims at reducing DUP- duration of untreated psychosis, treating the prodromal symptoms, treating the FEP – First- episode psychosis, and clinical management.
The staging model and its application in early psychosis
This model is a sophisticated diagnostic system that defines the progression of the disorder and guides the clinician in selecting treatments that best meet a specific stage.
Addressing clinical staging in diagnosis and intervention in early psychosis recognizes the need for conceptualizing psychopathology in the context of a neurodevelopmental framework. It is a prevention-oriented framework.
Table 1 Framework of the clinical staging model for psychotic disorders (modified from McGorry et al, 2006)
As shown in Table 1: the stage 1-2, progression to psychosis can be prevented, from stage 0-1b there is the emergence of undifferentiated symptoms and a decrease in functioning, stage 1b = UHR (Ultra High Risk) – subclinical symptoms (Prodrome + functional decline).
In Stage 2 we refer to FEP – First- episode psychosis, in stages 3a-3c, incomplete remissions, relapses and in stage 4 to chronic schizophrenia.
The Ultra High-Risk (UHR) Model
In the past, Ultra High Risk model was based on recruiting high genetic risk cases (first-degree relatives with psychosis) that had psychopathological disorders. Predictive power was low and there were many false-positive cases, the risk of developing psychosis being of 10-20% (Cannon, Mednich 1993 Erlenmeyer-Kimling 1997; Johnstone et al 2001).
Thus, at present, UHR criteria involve inclusion of a person in one or more of the following groups:
- APS-Attenuated Psychosis Symptoms Syndrome: patients who had subclinical attenuated positive psychotic episodes in the last year;
- BLIPS – Brief Limited Intermittent Psychotic Symptoms Syndrome: includes patients who experience psychotic intermittent, limited, short symptoms: patients who had psychotic episodes that lasted no more than a week and remitted spontaneously;
- GRD – Genetic Risk Deterioration Syndrome – Characteristics group and risk factors include patients who have a first-degree relative with a psychotic disorder or with schizotypal personality disorder, and who suffered a significant decrease in functionality in the previous year.
In Table 2, predictors for increased rate of conversion to psychosis can be found, within the category of ultrahigh risk.
In this context, it is the problem of observation, detection or intervention in the case of ultrahigh-risk group (UHR).
Identification in early symptomatic stages represents the basis of effective intervention strategies. In existing studies, the risk of conversion to psychosis in prodromal phase without treatment was observed as being of 41% in 12 months and of 50% within 24 months.
Conversion to psychosis is not the only risk associated with ultrahigh-risk group, UHR: 30% of cases develop another Axis I DSM disorder: affective disorders, anxiety disorders (Yung et al) and 29% do not develop other psychiatric disorder after 1 year.
Regarding the current treatment approaches for UHR-categories with ultrahigh risk, recent guidelines certify that persons who meet UHR criteria – “ultrahigh risk”- and seek help should be provided with:
- Regular monitoring,
- Treatments, including CBT, targeting anxiety, depression and relationship difficulties,
- Family support and education,
- Education about mental health, psychosis and coping strategies,
- It is recommended that these interventions should be made in an unrestrictive and un-stigmatizing framework.
Modern Therapeutic Approaches in Psychoses correlated with pharmacogenetic testing
Clinical experience suggests that the patient’s response to atypical and typical antipsychotic pharmacotherapy records an inter-individual variability. Variability of the response to atypical and typical antipsychotics correlates significantly with and metabolic polymorphisms [4, 17, 38].
By pharmacogenetic testing, the effects of genetic variation on response to medication safety, tolerability and efficacy are investigated. These genetic variants (mutations in the genome) – polymorphisms, are accountable for the response to medication [3, 10, 25, 26, 32].
Pharmacogenomics is the study of the application of genetic variability in drug response [1, 4, 8, 10, 11, 13, 17, 38].
Much of psychiatric medication is metabolized at the level of the enzymes of the cytochrome P450-CYP2D6 and CYP2C19. They exhibit genetic polymorphisms that cause changes in enzyme metabolic activity. Thus, the answer to antipsychotics is correlated with the genotype and enzyme activity. Within the general population, we discuss about four categories of metabolisers: poor, intermediate, extensive and ultra-rapid – Figure 1 [6, 24]….
Figure 1 Types of metabolisers
Figure 1 illustrates the way in which the types of metabolizers influence the response to antipsychotic / antidepressant medication.
Clinical applications concerning the response to antipsychotic / antidepressant medication
Lack of response to medication
Decrease of compliance to treatment
Genetic polymorphisms with clinical significance at the level of P450 cytochrome enzymes that are responsible for the metabolism of most antidepressants and antipsychotic medication are at the level of CYP2D6, CYP3A4, CYP2C19, CYP1A2.
In addition, the concentrations of the administered antipsychotic found in various types of metabolizers differ, as shown in Figure 3:
Figure 3 Plasmatic concentrations in antipsychotic medication in poor metabolisers (●) and in extensive metabolisers (○).
The clinical implications of pharmacogenetic testing in psychoses in children and adolescents depend on the level of metabolization of the medication. Thus, 50% of the anti psychotics metabolize at the level of CYP2D6, 23% at the level of CYP3A4, 18% at the level of and CYP1A2, and of the antidepressants – 85% at the level of CYP2D6, 38% at the level of CYP3A4 and 24% the level of CYP1A2.
In Figure 4, we find which are the CYP450 enzymes responsible for the metabolization of typical and atypical antipsychotics, respectively of antidepressants, [12, 16, 19].
Figure 4 CYP450 enzymes responsible for metabolism of typical and atypical antipsychotics, and of antidepressants
Currently, atypical antipsychotics are the treatment of choice for patients diagnosed with schizophrenia or bipolar disorder .
In Figure 5, we see again, which are the CYP450 enzymes responsible for the metabolization of atypical antipsychotics.
Figure 5 CYP450 enzymes responsible for metabolism of atypical antipsychotics
Clinical implications of pharmacogenetic testing in psychoses in children and adolescents
Existing studies suggest that certain variants of the gene CYP have a great impact on the response to antipsychotics, on tolerance and on adverse effects [1, 5, 7].
Poor metabolizers, are at increased risk for adverse effects (extrapyramidal symptoms, akathisia, dystonia, NMS – neuroleptic malignant syndrome, QTc prolongation on ECG, sedation, weight gain, hyperinsulinemia, metabolic syndrome, elevated prolactin).
CYP testing is necessary to adjust the dose of medication or to avoid the antipsychotics metabolized by the respective CYP, at which we find genetic polymorphisms. Thus, there are different polymorphisms – SNP (Single Nucleotide Polymorphism) which has been identified that it correlates with the clinical evolution of patients receiving treatment with atypical antipsychotics [1, 5, 7, 17, 18, 21, 22, 32, 38].
The atypical key antipsychotics metabolised by CYP2D6 are risperidone and aripiprazole [4, 8, 11, 15, 16, 35]. It has also been reported that serum concentrations of risperidone, aripiprazole, and olanzapine even vary considerably among patients with different CYP2D6 genotypes [4, 8, 15, 16, 17, 35].
Practical implications of pharmacogenetic testing are:
Avoiding antipsychotics metabolized by CYP2D6 in patients with polymorphisms – SNP genotype or WT / SNP genotype in poor metabolisers, too.
Avoiding especially risperidone, aripiprazole and haloperidol.
Choosing quetiapine, ziprasidone, possibly olanzapine or clozapine.
Some antidepressants should be avoided especially SSRIs that inhibit serotonin reuptake, and Valdoxan, lacking CYP2D6 passage, may be advisable in those who have polymorphisms at this level.
In ultra-rapid metabolizers, doses should be adjusted to obtain response to antipsychotic medication.
Regarding pharmacogenetics of antidepressant treatments, it is important to perform testing to see which patients would have non-response to certain antidepressants, since it generally takes about 6 weeks until an answer is noted and 40% of patients show insufficient response.
For this category of patients, possible polymorphisms in the gene should be identified too, for serotonin receptors- 5HTR2A and 5HTR2C. It is also possible to identify the genotypes WT / -759C / T and SNPs.
In some patients, -795C / T, cause multiple adverse reactions to SSRI-type antidepressants (high weight gain). Therefore, in these patients such antidepressants should be avoided.
The CYP genotyping allows customization of therapy based on each individual’s particular genetic patterns
When choosing the drug therapy in psychosis in children and adolescents, we should consider the following algorithm, which, when pharmacogenetic testing completes it, facilitates rapid selection of appropriate pharmacotherapy and brings new perspectives on the patients’ quality of life of and on cost-benefit balance – Figure 6, Figure 7.
Figure 6 Pharmacotherapy of first-episode non-affective psychosis
Figure 7 Pharmacotherapy of first episode affective psychosis
Regarding the pharmacotherapy of drug resistance, we have the classic algorithm of decision in Figure 8 (FGA = first generation antipsychotics and SGA = second generation antipsychotics). Of course some of the problems we face in case of resistance to treatment could be avoided by pharmacogenetic testing prior to prescribing pharmacotherapy.
Figure 8 Pharmacotherapy of drug resistance
CYP2D6 genotyping allows customization of therapy based on genetic patterns specific to each individual [2, 4, 6, 8, 18, 23, 24, 31, 38]. In this context, the pharmacogenetics of response to antipsychotic medication is a promising perspective in choosing appropriate treatment, adapted to the individual patient, and avoiding the lack of efficacy of the clinical response, as well as significant side effects [9, 10, 27, 32, 33].
In particular, in the paediatric population, which entails greater risks due to metabolic peculiarities and other factors, this aspect of pharmacogenetics should be addressed very carefully [2, 23, 28, 29, 30, 34, 36, 37]. Greater attention should also be given to drug interactions due to polymorphisms and to the metabolic pharmacogenomic information.
Thus, the response to antipsychotic medication correlates with CYP genotyping, with polymorphisms in the CYP level, affecting the effectiveness of medication and the clinical evolution [11, 13, 14, 15, 20]. It is necessary to study this aspect in the paediatric population where there are not many studies [3, 12, 13, 18, 19].
Being in the developmental period, the whole trajectory of paediatric patients could be compromised due to lack of efficacy or a bad response to the chosen antipsychotic drug. For this category of patients, especially, medication safety issues are crucial, therefore the study of the genetic mechanisms underlying adverse drug reactions can bring significant benefits to patients, facilitating the process of choosing the best pharmacotherapy, with the expectancy of the fewest side effects [21, 23, 29, 30].
This poor response to medication, in particular to the antipsychotic correlated with polymorphisms in the CYP level, could explain why many psychotic patients are resistant or non-responding to medication from the clinical point of view. [5, 23, 26, 31].
Pharmacogenetics is a future perspective in usual clinical practice as a pharmacotherapy that is tailored, individualized, personalized, targeted, would be more efficient and ethically adequate, especially for the paediatric population [9, 10, 14, 21, 30, 34, 36].
We must confer attention to the fact that a bad response to medication and lack of efficacy will be followed by the non-compliance of the patient [28, 36, 37].
Today, we stepped into the era of a personalized medicine, a medicine based on individual genetic patterns and the focus is on deciphering the mechanisms that might explain individual variability of response to pharmacotherapy and on identifying the pharmacokinetic and pharmacodynamic biomarkers that are useful in clinical practice [10, 38 ].
Using optimal treatment presents numerous economic implications, too, reducing management costs in psychosis in children and adolescents [9, 17, 18, 21, 28].
Management of psychoses requires a differentiated and integrative approach to each case, initiated as early as possible in a multidisciplinary team that should act flexibly, coherently synergistically and co-ordinately.
The purpose of detection and early intervention is capturing patients in a more responsive phase, aiming at reducing the duration of untreated psychosis.
Specific interventions will be based on evidence, in relation to clinical staging, taking into account the critical period of maximum vulnerability.
Services and interventions will focus on family, making up the pyramid of needs.
It is important to create an interface between mental health services for children and those for adults, particularly in cases of “High Risk”.
By pharmacogenetic testing and screening, genotypes and genetic polymorphisms can be identified that determine individual response to pharmacotherapy in child and adolescent psychoses.
This is the key to medicine that is personalized, individualized, and tailored to the patient.
Since paediatric patients with psychosis are in development, their entire developmental trajectory may be compromised due to lack of efficacy of therapy.
For this category in particular, the issue of drug safety is crucial, so studying the genetic mechanisms underlying adverse reactions to medication, can bring significant benefits, helping clinicians in the selection of the most appropriate therapies with fewer side effects involved.
Pharmacogenetics is a future perspective in current clinical practice since an individualized, personalized, therapy that is adapted to the patient’s needs should be chosen as first-line therapy.
It is also an ethical issue, especially in children, because instead of making a permanent switch to antipsychotics, it is more efficient to implement targeted interventions and pharmacotherapy.
As a future perspective, CYP pre-screening should be performed before the prescription of an antipsychotic and of medication in the psychoses in children and adolescents.
Using optimal treatment has economic implications, too, reducing case management costs in psychosis of children and adolescents.
The emergence of pharmacogenetics as a modern approach marks a new stage in clinical psychiatry, where biomarkers and genotype influence the choice of therapy, increasing the safety and efficacy of used medication.
More research is needed to develop a genetically informed medicine, which is also customized; in addition, clinical studies are needed to prove the efficacy, tolerability and safety of pharmacotherapy administered in psychoses of paediatric patients.
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