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Psychoses on the Schizophrenia Spectrum in Adolescence: A Cross-sectional Study of Factors Influencing Neuropsychology, Treatment Outcome, and Negative Symptoms Abstract: The present study evaluated the factors influencing the course of disease of children and adolescents in an inpatient rehabilitation suffering from psychosis within the schizophrenia spectrum. Objective: The present study evaluated the factors influencing the course of disease of children and adolescents in an inpatient rehabilitation suffering from psychosis within the schizophrenia spectrum. Methods: 33 patients (mean age 19.4 years, SD = 2.3), 12 of (36 %) were female, participated. They were assessed with clinical interviews (IRAOS, SANS/SAPS), neuropsychological tests (WAIS-IV, TMT), and questionnaires (FBB, BSCL). Results: The neuropsychological functioning level and the premorbid cognitive performance were correlated, as were treatment success from the patient's perspective with a good relationship with the therapist, and greater negative symptomatology with a longer duration of untreated psychosis (DUP) and a longer initial hospital stay. Conclusion: Possible approaches to improving the treatment of adolescents with psychosis of the schizophrenic spectrum include a shortening of the DUP and a good therapeutic relationship.

Findings of genetic overlap between Schizophrenia, Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) contributed to a renewed conceptualization of these disorders as laying on a continuum based on aetiological, pathophysiological and neurodevelopmental features. Given that cognitive impairments are core to their pathophysiology, we compared patients with schizophrenia, ADHD, ASD, and controls on ocular-motor and manual-motor tasks, challenging crucial cognitive processes. Group comparisons revealed inhibition deficits common to all disorders, increased intra-subject variability in schizophrenia and, to a lesser extent, ADHD as well as slowed processing in schizophrenia. Patterns of deviancies from controls exhibited strong correlations, along with differences that posited schizophrenia as the most impaired group, followed by ASD and ADHD. While vector correlations point towards a common neurodevelopmental continuum of impairment, vector levels suggest differences in the severity of such impairment. These findings argue towards a dimensional approach to Neurodevelopmental Disorders' pathophysiological mechanisms., (© 2022. The Author(s).)

Disorders with neurodevelopmental aetiology such as Attention-Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD) and Schizophrenia share commonalities at many levels of investigation despite phenotypic differences. Evidence of genetic overlap has led to the concept of a continuum of neurodevelopmental impairment along which these disorders can be positioned in aetiological, pathophysiological and developmental features. This concept requires their simultaneous comparison at different levels, which has not been accomplished so far. Given that cognitive impairments are core to the pathophysiology of these disorders, we provide for the first time differentiated head-to-head comparisons in a complex cognitive function, visual search, decomposing the task with eye movement-based process analyses. N = 103 late-adolescents with schizophrenia, ADHD, ASD and healthy controls took a serial visual search task, while their eye movements were recorded. Patients with schizophrenia presented the greatest level of impairment across different phases of search, followed by patients with ADHD, who shared with patients with schizophrenia elevated intra-subject variability in the pre-search stage. ASD was the least impaired group, but similar to schizophrenia in post-search processes and to schizophrenia and ADHD in pre-search processes and fixation duration while scanning the items. Importantly, the profiles of deviancy from controls were highly correlated between all three clinical groups, in line with the continuum idea. Findings suggest the existence of one common neurodevelopmental continuum of performance for the three disorders, while quantitative differences appear in the level of impairment. Given the relevance of cognitive impairments in these three disorders, we argue in favour of overlapping pathophysiological mechanisms., (© 2021. The Author(s).)

Cross-sectional data of inpatient residents of a rehabilitation center with schizophrenic psychosis diagnosis Abstract., Objective: The objective of this study is to evaluate the level of neuropsychological functioning, quality of life, content of treatment, abnormal psychology as well as the level of functioning and medication in children and adolescents who suffer from a schizophrenia spectrum disorder, treated as rehabilitation inpatients., Methods: Forty-two patients could be examined, therefore, the IRAOS, the WAIS-IV, the TMT-A/-B, the FBB-P (patient's version), the ILK-P, the SANS/SAPS, the BPRS, the BSCL, the GAF, the CGAS, and the CGI were used., Results: Patients' average age at onset of the disorder was 14.49 years (± 2.90). The total value of IQ was 87.00 (± 15.02), the value of TMT-A was 73.05 (± 14.51), and of the TMT-B 75.62 (± 15.15). The value for the content of treatment in the summary-score of the FBB-P was 3.05 (± 0.49). The value of the total-score in ILK-P was 2.10 (± 0.70). The summary-score of the SANS was 5.00 (± 2.90) and of the SAPS 3.00 (± 2.70). The BPRS-summary-score's value was 30.70 (± 7.80), the BSCL-GSI's value was 0.90 (± 0.50). GAF and CGAS were at 48.30 (± 12.80), respectively 51.00 (± 12.30). Clozapin has been prescribed in 25.0 % of the cases as first or second neuroleptic medication., Conclusion: We investigated patients with VEOS and EOS living in a rehabilitation center. Usually, the course of their illness is much more severe and chronic than it is seen in a common department for child and adolescent psychiatry. Findings indicate a clear impairment in the level of neuropsychological and global functioning in contrast to rather low to moderate burden of positive/negative deficits. Satisfactory results of treatment and quality of life could be evaluated in spite of the aforementioned impairments. Medication did not conform to current guidelines, especially concerning Clozapin. Findings of the subsequent follow-up will show, if the impairment will improve under inpatient rehabilitation conditions.

Objective: To examine relations between movement disorders (MD) and psychopathological symptoms in an adolescent population with schizophrenia under treatment with predominantly atypical antipsychotics., Method: MD symptoms and psychopathology were cross-sectionally assessed in 93 patients (aged 19.6 +/- 2.2 years) using Tardive Dyskinesia Rating Scale (TDRS), Abnormal Involuntary Movement Scale (AIMS), Extrapyramidal Symptom Scale (EPS), Barnes Akathisia Scale (BAS), Brief Psychiatric Rating Scale (BPRS) and the Schedule for Assessment of Negative/Positive Symptoms (SANS/SAPS)., Results: All patients with MD symptoms (n = 37; 39.8 %) showed pronounced global psychpathological signs (SANS/SAPS, BPRS: p = 0.026, p = 0.033, p = 0.001) with predominant anergia symptoms (p = 0.005) and inclinations toward higher anxiety- and depression-related symptoms (p = 0.051) as well as increased thought disturbance (p = 0.066). Both negative symptoms and anergia showed trends for positive correlations with tardive dyskinesia (p = 0.068; p = 0.065) as well as significant correlations with parkinsonism symptoms (p = 0.036; p = 0.023). Akathisia symptoms correlated significantly with hostile and suspicious symptoms (p = 0.013). A superfactor-analysis revealed four factors supporting the aforementioned results., Conclusion: MD symptoms and psychopathology are in some respects related to each other. Motor symptoms representing on the one hand trait characteristics of schizophrenia might additionally be triggered by antipsychotics and finally co-occur with more residual symptoms within a long-term treatment.

Objective: To examine prevalence of movement disorders (MDs) such as tardive dyskinesia (TD), parkinsonism or akathisia in an adolescent population with schizophrenia and in relationship to predominantly atypical antipsychotic treatment., Method: Ninety-three patients (aged 19.6+/-2.2 years) were ascertained in this cross-sectional/retrospective study. 76 patients (81.7%) received atypical, 10 (10.8%) typical antipsychotics and 7 (7.5%) combinations of atypical/typical antipsychotics. MD symptoms were assessed using Tardive Dyskinesia Rating Scale (TDRS), Abnormal Involuntary Movement Scale (AIMS), Extrapyramidal Symptom Scale (EPS), Barnes Akathisia Scale (BAS)., Results: Movement disorder symptoms were found in 37 patients (39.8%) fulfilling strict/subthreshold criteria for TD (5.4/11.8%), parkinsonism (2.2/25.8%) or akathisia (1.1/11.8%), respectively. Patients treated with typical antipsychotics displayed a significantly higher EPS-score (P=0.036) and a tendency towards a higher BAS-score (P=0.061) compared to patients with atypical antipsychotics. Treatment durations with typical/atypical antipsychotics showed trends towards advantages of atypical antipsychotics with regard to parkinsonism/akathisia symptoms (P=0.061; P=0.054), but not with regard to TD symptoms (P=0.003), possibly due to confounding effects., Conclusion: Under treatment with atypical antipsychotics MD symptoms are less prevalent and less pronounced than under typical antipsychotics. We speculate that the finding of relatively high prevalence rates of subthreshold MD symptoms may be, at least partially, explained by previous or combined therapy with typical antipsychotics.

Our study investigated premorbid functioning, course, and outcome in early-onset schizophrenia. All inpatients with DSM-III-R diagnoses of schizophrenia (n = 101) consecutively admitted between 1983 and 1988 to the Department of Child and Adolescent Psychiatry at the University of Marburg in Germany were included. To assess premorbid adaptation and precursor symptoms, we administered the Instrument for the Retrospective Assessment of the Onset of Schizophrenia, which we modified to assess children and adolescents. Symptomatology was measured by the Scale for the Assessment of Negative Symptoms, the Scale for the Assessment of Positive Symptoms, and the Brief Psychiatric Rating Scale. In addition, the Global Assessment of Functioning was applied. Followup data for 81 patients (80.2%) were available. The mean duration of schizophrenia at followup was 9.5 +/- 2.2 years. Assessment of the highest level of adaptive functioning revealed very good or good outcome in 19.8 percent of the patients, fair or poor outcome in 38.2 percent, and very poor outcome and gross impairment in 42.0 percent. Premorbid adjustment was the best predictor of outcome in our schizophrenia sample. A poor prognosis was found in patients with premorbid developmental delays and those who were introverted and withdrawn before their psychotic state.

Objectives: The relation between substance abuse and symptoms of psychosis as well as related disorders was evaluated among patients at the Hospital for Child and Adolescent Psychiatry and Psychotherapy of the University of Marburg., Methods: Using a child and adolescent version of the IRAOS (Instrument of the Retrospective Assessment of the Onset of Schizophrenia, Häfner et al., 1990), all patients with a co-morbid substance abuse were assessed. Patients with a drug-induced psychosis (n = 8) were compared to psychotic patients with co-morbid substance abuse and to patients with other psychiatric disorders and substance abuse (n = 30)., Results: These three groups could be significantly distinguished on the basis of pre-morbid symptoms and pre-morbid functioning., Conclusions: The IRAOS shows some evidence that psychotic patients with co-morbid substance abuse can be distinguished from patients with a drug-induced psychosis according to the course of the initial psychopathology and pre-morbid functioning.

Clozapine is a dibenzodiazepine derivative with established antipsychotic efficacy in adult patients with schizophrenic psychoses. There are more than 15 studies that have also demonstrated the antipsychotic efficacy of clozapine in childhood and adolescent schizophrenia. The main advantages of clozapine treatment in this age group in comparison with typical antipsychotics are: (i) high antipsychotic efficacy during an acute schizophrenic episode; (ii) better improvement in chronic cases with a high load of negative symptoms; and (iii) markedly fewer extrapyramidal adverse effects and, therefore, fairly good tolerability. However, because of its possible adverse effects on the haemopoetic system (granulocytopenia, agranulocytosis), clozapine should not be used as first-line antipsychotic medication. Other adverse effects are related to the cardiovascular system (hypotonia, tachycardia or arrhythmia), the central nervous system (epileptic seizures, fever) and liver function (transient increases in levels of hepatic transaminases). Two other frequent adverse effects are hypersalivation and body-weight gain, which may present a particular problem in adolescents and young adults. Careful monitoring of haematological parameters and other adverse effects are preconditions for a successful treatment programme.

Objectives: The purpose of this study was to assess the relationships between neuroleptic medication, biogenic amines and symptomatology in a sample of adolescents with schizophrenia (ICD-10 critria)., Method: Psychopathological symptoms were rated weekly by means of standard rating scales (BPRS, SANS, SAPS), parallel to weekly blood samplings for measurement of biogenic amines and serum levels of clozapine. These measures were obtained for the 6 weeks of conventional neuroleptic treatment and the subsequent 6-week open-label clozapine trial., Results: Serum levels of serotonin and plasma norepinephrine were significantly higher during treatment with clozapine than during pretreatment with typical neuroleptics. A comparison of the plasma norepinephrine levels in responders (n = 7) and non-responders (n = 8) to those of clozapine revealed that response to clozapine can be predicted on the basis of the epinephrine levels prior to initiation of clozapine treatment. Additionally, plasma concentrations of methoxyhydroxyphenylglycol (MHPG) and epinephrine were both increased in clozapine responders in comparison to the levels measured during pretreatment with typical neuroleptics. Finally, our results demonstrate that depressive symptomatology prior to initiation of clozapine treatment is also predictive of response to this atypical neuroleptic, schizophrenia.

Weight gain is a major side-effect of treatment with clozapine. In order to investigate the influence of the atypical neuroleptic clozapine on leptin secretion, serum leptin levels were measured in 12 patients at baseline and for a 10-week period after initiation of treatment. Serum clozapine levels and levels of its metabolites were simultaneously assessed. Alterations of body weight and body composition were determined. During the 10-week observation period leptin levels differed significantly from the levels determined at baseline (P < 0.0001). During the first 2 weeks of treatment serum leptin levels at least doubled in eight of the 12 patients. The maximal relative increase over baseline was 536%. Low doses of clozapine were sufficient to induce this effect. Within a 10-week period mean body weight, mean body mass index, mean fat mass and mean lean body mass all increased. Based on the results we suggest that in predisposed individuals clozapine induces an increased appetite; overeating and weight gain can ensue, which in turn underlie elevated leptin secretion.

The aims of this investigation were to evaluate long-term and short-term effects of clozapine-treatment on plasma biogenic amines and psychopathology measures in adolescents with schizophrenia (DSM-III-R criteria). The long-term study was conducted in a study sample of 40 young patients (age 14-22 years) following a mean of 3.4 years of neuroleptic treatment. During the study, 20 patients received clozapine, and the other 20 patients were treated with standard neuroleptic medications. At the beginning of the open clinical trials, the patients had already been receiving clozapine treatment for 24 +/- 15 months. Assessment of the biochemical and psychopathological measures was performed on six occasions at consecutive 6-week intervals during maintenance treatment with clozapine or conventional neuroleptics. Blood levels of serotonin, 3-methoxy-4-hydroxy-phenylglycol (MHPG), norepinephrine, and epinephrine were significantly higher in clozapine-treated patients than in conventionally treated patients. During long-term treatment, higher serotonin levels were associated with significantly fewer negative symptoms of schizophrenia, whereas higher MHPG levels were correlated with less depression. The short-term effects of clozapine were assessed in a second and independent study sample. After failing on conventional neuroleptics in clinical trials lasting a mean of 1.6 years, 15 inpatients (aged 11-20 years) received clozapine. Weekly ratings of psychopathological symptoms using standard rating scales were performed in parallel to blood samplings for measurements of biogenic amines and serum levels of clozapine. These measures were obtained for 6 weeks during conventional neuroleptic treatment and for 6 weeks during the open-label clozapine trial. Serum levels of serotonin and plasma norepinephrine levels were significantly higher during treatment with clozapine than during pretreatment with typical neuroleptics. A comparison of plasma epinephrine levels in responders (n = 7) and nonresponders (n = 8) to clozapine revealed that response to clozapine can be predicted by epinephrine levels prior to initiation of treatment with clozapine (responders ranging from 32.2 to 90.3 pg/ml; nonresponders ranging from 92.5 to 473.5 pg/ml). Additionally, subjects who responded to clozapine showed increased mean plasma concentrations of MHPG and epinephrine during treatment with this drug in comparison to the levels measured during pretreatment with typical neuroleptic medication. Nonresponders to clozapine failed to show this increase. Finally, in responders to clozapine a negative linear relationship between negative symptoms of schizophrenia and the concentrations of plasma norepinephrine and serum serotonin were observed. In conclusion, our results demonstrate that plasma epinephrine levels prior to initiation of clozapine therapy predict response to this atypical neuroleptic. Our findings derived from short-term and maintenance treatment with clozapine suggest involvement of norepinephrine, epinephrine and serotonin in the therapeutic actions of the atypical neuroleptic clozapine.

A study of 40 young patients (age 14-22 years) with DSM-III-R schizophrenia (without substance abuse) was conducted following a mean of 3.4 years of neuroleptic treatment. After failing on conventional agents in clinical trials lasting a mean of 2 years, 20 patients were prospectively maintained on open-label clozapine (mean 324 mg daily), and another 20 patients continued on typical neuroleptics (mean 465 mg chlorpromazine-equivalents daily). Patients were then sampled for biochemical measures and assessed for psychopathology (Brief Psychiatric Rating Scale, Scales for the Assessment of Positive/ Negative Symptoms) on six occasions at consecutive 6-week intervals-during maintenance treatment on clozapine or conventional neuroleptics. There were 22-fold interindividual differences in clozapine levels and also high intraindividual differences over time. Maintenance dosage was linearly related to plasma levels of clozapine and its metabolites. Prolactin levels were elevated with typical neuroleptics but not clozapine. Blood levels of serotonin, methoxyhydroxyphenylglycol (MHPG), norepinephrine, and epinephrine (but not dopamine) were significantly higher in clozapine-treated patients than in conventionally treated patients. Higher serotonin levels were associated with significantly fewer negative symptoms, whereas higher MHPG levels were correlated with less depression. These findings suggest involvement of norepinephrine and serotonin in the pathophysiology of schizophrenia (with depression associated with lower MHPG levels and negative symptoms associated with lower serotonin levels) and in the therapeutic actions of clozapine. Speculatively, a treatment strategy of targeting specific neurotransmitter systems might be based on the presence of specific symptoms in adolescents and young adults with schizophrenia.

This report describes a method for determination of clozapine and its major metabolites N-desmethylclozapine and clozapine N-oxide in serum samples of adolescent schizophrenic patients during maintenance therapy. The method includes deproteinization and subsequent high-performance liquid chromatography with electrochemical detection. The method shows sufficient sensitivity to quantitate clozapine, clozapine N-oxide and N-desmethylclozapine accurately at 0.5, 5, and 0.5 ng/ml, respectively. We were able to demonstrate for 16 patients receiving fixed doses of clozapine that the individual mean values calculated from six consecutive measurements revealed a strong linear dosage and serum level relationship (Pearson's coefficient of correlation): clozapine (r = 0.82, p = 0.0001); N-desmethylclozapine (r = 0.81, p = 0.0001); clozapine N-oxide (r = 0.91; p = 0.0001). Preliminary pharmacokinetic data are presented and dose-response relationship are discussed.

Longitudinal assessments (every six weeks for one year) were made of plasma norepinephrine, dopamine, epinephrine and 3-methoxy-4-hydroxyphenylglycol (MHPG) in 40 adolescents with schizophrenia, 20 on clozapine therapy and 20 on conventional medication. In addition to the plasma catecholamine determinations, serum levels of 5-HT were determined as a measure of serotoninergic status. All analyses were performed by HPLC-ECD (high-performance liquid chromatography with electrochemical detection). Clinical ratings of symptomatology were obtained with the Brief Psychiatric Rating Scale (BPRS) and the Andreasen scales for negative and positive symptoms (SANS and SAPS). Compared with the typical neuroleptic medication, clozapine administration was accompanied by a significant increase in plasma norepinephrine and MPHG and serum serotonin levels. The fluctuations in the biogenic amines were closely associated with the observed symptomatology. Plasma MHPG was linked to depressive symptoms (BPRS), and negative symptoms (SANS) were related to changes in the serum serotonin levels. The pathophysiological implications and clinical consequences of these findings are discussed.