Anne Katrine Pagsberg

Basal ganglia volumes in drug-naive first-episode schizophrenia patients before and after short-term treatment with either a typical or an atypical antipsychotic drug

The present study examined basal ganglia volumes in drug-naive first-episode schizophrenic patients before and after treatment with either a specific typical or atypical antipsychotic compound. Sixteen antipsychotic drug-naive and three minimally medicated first-episode schizophrenic patients and 19 matched controls participated. Patients were randomly assigned to treatment with either low doses of the typical antipsychotic drug, zuclopenthixol, or the atypical compound, risperidone. High-resolution magnetic resonance imaging (MRI) scans were obtained in patients before and after 12 weeks of exposure to medication and in controls at baseline. Caudate nucleus, nucleus accumbens, and putamen volumes were measured. Compared with controls, absolute volumes of interest (VOIs) were smaller in patients at baseline and increased after treatment. However, with controls for age, gender and whole brain or intracranial volume, the only significant difference between patients and controls was a Hemisphere x Group interaction for the caudate nucleus at baseline, with controls having larger left than right caudate nuclei and patients having marginally larger right than left caudate volumes. Within patients, the two medication groups did not differ significantly with respect to volume changes after 3 months of low dose treatment in any of the VOIs. Nevertheless, when medication groups were examined separately, a significant volume increase in the putamen was evidenced in the risperidone group. The altered asymmetry in caudate volume in patients suggests intrinsic basal ganglia pathology in schizophrenia, most likely of neurodevelopmental origin.

Clinical Characteristics and Predictors of Outcome of Schizophrenia-Spectrum Psychosis in Children and Adolescents: A Systematic Review

OBJECTIVEnTreatment of early-onset schizophrenia spectrum psychosis (EOS) is hampered by limited data on clinical presentation and illness course. We aimed to systematically review the clinical characteristics, diagnostic trajectories, and predictors of illness severity and outcomes of EOS.nnnMETHODSnWe conducted a systematic PubMed, PsycINFO, and Embase literature review including studies published from January 1, 1990 to August 8, 2014 of EOS patients with 1) ≥50% nonaffective psychosis cases; 2) mean age of subjects <19 years; 3) clinical samples recruited through mental health services; 4) cross-sectional or prospective design; 5) ≥20 participants at baseline; 6) standardized/validated diagnostic instruments; and 7) quantitative psychotic symptom frequency or severity data. Exploratory analyses assessed associations among relevant clinical variables.nnnRESULTSnAcross 35 studies covering 28 independent samples (nu2009=u20091506, ageu2009=u200915.6 years, age at illness onsetu2009=u200914.5 years, malesu2009=u200962.3%, schizophrenia-spectrum disordersu2009=u200989.0%), the most frequent psychotic symptoms were auditory hallucinations (81.9%), delusions (77.5%; mainly persecutory [48.5%], referential [35.1%], and grandiose [25.5%]), thought disorder (65.5%), bizarre/disorganized behavior (52.8%), and flat or blunted affect/negative symptoms (52.3%/50.4%). Mean baseline Positive and Negative Syndrome Scale (PANSS)-total, positive, and negative symptom scores were 84.5u2009±u200910.9, 19.3u2009±u20094.4 and 20.8u2009±u20092.9. Mean baseline Clinical Global Impressions-Severity and Childrens Global Assessment Scale/Global Assessment of Functioning (CGAS/GAF) scores were 5.0u2009±u20090.7 and 35.5u2009±u20099.1. Comorbidity was frequent, particularly posttraumatic stress disorder (34.3%), attention-deficit/hyperactivity and/or disruptive behavior disorders (33.5%), and substance abuse/dependence (32.0%). Longer duration of untreated psychosis (DUP) predicted less CGAS/GAF improvement (pu2009<u20090.0001), and poor premorbid adjustment and a diagnosis of schizophrenia predicted less PANSS negative symptom improvement (pu2009=u20090.0048) at follow-up. Five studies directly comparing early-onset with adult-onset psychosis found longer DUP in EOP samples (18.7u2009±u20096.2 vs. 5.4u2009±u20093.1 months, pu2009=u20090.0027).nnnCONCLUSIONSnEOS patients suffer substantial impairment from significant levels of positive and negative symptoms. Although symptoms and functioning improve significantly over time, pre-/and comorbid conditions are frequent, and longer DUP and poorer premorbid adjustment is associated with poorer illness outcome.

Early Nonresponse Determined by the Clinical Global Impressions Scale Predicts Poorer Outcomes in Youth with Schizophrenia Spectrum Disorders Naturalistically Treated with Second-Generation Antipsychotics

OBJECTIVEnThe use of early response/nonresponse (ER/ENR) to antipsychotics as a predictor for ultimate response/nonresponse (UR/UNR) may help decrease inefficacious treatment continuation. However, data have been limited to adults, and ER/ENR has only been determined using time-consuming psychopathology rating scales. In the current study, we assessed if early improvement on the Clinical Global Impressions-Improvement (CGI-I) scale predicted UR/UNR in psychiatrically ill youth started on antipsychotic treatment.nnnMETHODSnSeventy-nine youth aged 6-19 years, with schizophrenia spectrum disorders, treated naturalistically with aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone and evaluated monthly, were divided into ER/ENR groups at week 4, using at least minimally improved on the CGI-I scale. Prediction using week 4 ER/ENR status for UR (CGI-I=at least much improved), effectiveness and adverse effect outcomes at 8-12 weeks were assessed.nnnRESULTSnAt 4 weeks, 45.6% of subjects were ER and 54.4% were ENR without differences regarding baseline demographic, illness, and treatment variables, except for higher age (p=0.034) and maximum risperidone dose (p=0.0043) in ENR. ER/ENR status at 4 weeks predicted UR/UNR at week 12 significantly (p<0.0001): Sensitivity=68.9%, specificity=85.3%, positive predictive value=86.1%, negative predictive value=67.4%. At weeks 4, 8, and 12, ER patients improved significantly more on the CGI-I, CGI-Severity, and Childrens Global Assessment of Functioning scales, and more ER patients reached UR compared with ENR patients (83.3% vs. 34.9%, all p<0.0001). ENR patients had more extrapyramidal side effects (EPS) at weeks 4, 8, and 12 (p=0.0019-0.0079). UR was independently associated with ER (odds ratio [OR]=18.09; 95% confidence interval [CI]=4.71-91.68, p<0.0001) and psychosis not otherwise specified (NOS) (OR=4.82 [CI: 1.31-21.41], p=0.017) (r(2)=0.273, p<0.0001).nnnCONCLUSIONSnOlder age and EPS were associated with ENR; ENR and schizophrenia were associated with UNR in naturalistically treated youth with schizophrenia spectrum disorders. Early CGI-I-based treatment decisions require further consideration and study.

Pretreatment Cardiometabolic Status in Youth With Early-Onset Psychosis: Baseline Results From the TEA Trial.

OBJECTIVEnTo describe pretreatment cardiometabolic constitution in children and adolescents with first-episode psychosis (FEP).nnnMETHODSnBaseline cardiometabolic assessment was performed in youths aged 12-17 years with FEP entering the Tolerability and Efficacy of Antipsychotics (TEA) trial and matched healthy controls. Patients were included between June 10, 2010, and January 29, 2014. ICD-10 was used as the diagnostic classification system. Cardiometabolic risk markers were compared between patients versus controls and antipsychotic-naive versus antipsychotic-exposed patients.nnnRESULTSnComparing 113 youths with FEP (age ± SD = 15.74 ± 1.36 years, males = 30.1%, schizophrenia-spectrum disorders = 92.9%, antipsychotic-naive: n = 57) to 60 controls, patients had higher waist circumference (WC) z scores (1.13 ± 1.65 vs 0.42 ± 1.27, P = .018), cholesterol (4.10 ± 0.71 vs 3.79 ± 0.49 mmol/L, P = .014), low-density lipoproteins (2.37 ± 0.56 vs 2.13 ± 0.51, P = .012), and non-high-density lipoproteins (2.58 ± 1.60 vs 2.52 ± 0.52, P = .018). More patients than controls (42.9% vs 20.3%, P = .019) and antipsychotic-naive than antipsychotic-exposed (51.9% vs 34.0%, P = .023) had a WC > 90th percentile. Hypercholesterolemia (34.0% vs 12.5%, P = .015) was more frequent in patients, while decreased high-density lipoprotein cholesterol was more frequent in controls (32.5% vs 19.0%, P = .032). Family history of type 2 diabetes mellitus was associated with increased body mass index (BMI) z score (P < .001), WC z score (P = .001), insulin (P = .038), and homeostatic model assessment of insulin resistance (HOMA-IR; P = .025). Dyslipidemia was associated with significantly increased insulin (P = .041), HOMA-IR (P = .032), and low-density lipoprotein cholesterol (P = .041). Previous antipsychotic exposure was not associated with increased cardiometabolic risk. Early age at onset predicted increased BMI and WC z scores, while diagnosis of schizophrenia and higher Clinical Global Impression-Severity score were associated with increased blood lipids.nnnCONCLUSIONSnYouths with FEP had significantly greater WC and lipid abnormalities than matched controls, regardless of antipsychotic exposure. In youths with FEP, elevated metabolic risk predates antipsychotic exposure.nnnTRIAL REGISTRATIONnClinicalTrials.gov identifier: NCT01119014; European Clinical Trials Database (EudraCT): 2009-016715-38u200bu200bu200b.

F34. AUDITORY SENSORY GATING IN YOUNG ADOLESCENTS WITH EARLY-ONSET PSYCHOSIS: A COMPARISON WITH ADHD

Abstract Background Numerous studies have demonstrated impaired sensory gating in schizophrenia and this phenomenon has been proposed as a candidate biomarker for the disorder. Sensory gating is typically assessed during an auditory paired-click test commonly referred to as a P50 suppression paradigm. When two identical stimuli are presented, healthy subjects show a decrease in their neural response to the second stimulus, reflected in a decreased P50 amplitude, whereas schizophrenia patients on average show a much smaller decrease. So far, sensory gating has primarily been investigated in adult patients with schizophrenia, but gating disturbances have also been demonstrated in other illnesses, e.g. in schizotypal personality disorder, albeit less marked. Although the typical age of onset for schizophrenia is late adolescence to early adulthood, a sizable group of patients presents with psychotic symptoms during childhood or early adolescence. Manifestation of psychotic symptoms before the age of 18 is commonly referred to as early-onset psychosis (EOP). Various studies have reported a more severe course of illness and a poorer outcome in EOP compared to the adult-onset form of the disorder. In parallel, we expect more pronounced sensory gating deficits in EOP. Impaired sensory gating may not be specific to psychosis, but rather a shared disturbance of neuropsychiatric disorders. Although symptoms of attention deficit hyperactivity disorder (ADHD) differ in many ways from those found in schizophrenia, there are common characteristics. Compared to schizophrenia, relatively few studies have investigated sensory gating in ADHD, and some report P50 gating deficits similar to those frequently found in patients with schizophrenia. Methods We investigated P50 suppression in a large cohort of adolescents (12–17 years old) consisting of patients with either EOP (N=56) or ADHD (N=28) as well as age and gender matched healthy controls (N=72). In our paradigm two identical sounds (clicks) were presented separated by a 500ms interval. The amount of suppression was expressed as the ratio between the P50 amplitude of a subject’s response to the first click and his/her amplitude in response to the second click. Results The EOP patients scored significantly higher on PANSS (positive, negative, general, and total PANSS scores) compared to both ADHD patients and healthy controls. However, there were neither significant group differences in raw P50 amplitude, nor in the gating ratios between young adolescents with EOP, ADHD and healthy controls. Discussion This is the first study to investigate sensory gating in young adolescents with EOP. We found no P50 suppression deficits in these patients which, given the relatively large sample size in our study, cannot merely be ascribed to power issues. The results are in contrast with the majority of studies investigating sensory gating in schizophrenia and ADHD. However, the results are in agreement with earlier studies from our lab showing evidence of inconsistent P50 suppression deficits in two separate cohorts of adult, antipsychotic naïve, first-episode patients with schizophrenia. Based on our findings, P50 sensory gating cannot differentiate between young adolescents with EOP or ADHD, and deficient P50 suppression does not seem to be a valid biomarker for EOP.