Mariken B. de Koning

Striatal dopamine D2/3 receptor binding following dopamine depletion in subjects at Ultra High Risk for psychosis.

Altered striatal dopaminergic neurotransmission is thought to be fundamental to schizophrenia. Increased presynaptic dopaminergic activity ([18F]-DOPA PET) may predate the onset of psychotic symptoms and correlates to clinical symptoms in subjects at Ultra High Risk (UHR) for developing psychosis. Postsynaptic dopaminergic neurotransmission has not been investigated yet in UHR patients. We hypothesized that synaptic dopamine concentration would be increased in UHR patients, and that synaptic dopamine concentration would be related to symptom severity. 14 UHR patients and 15 age and IQ matched controls completed an [123I]-IBZM SPECT scan at baseline and again after dopamine depletion with alpha-methyl-para-tyrosine (AMPT). We measured changes in radiotracer binding potential, compared these between UHR patients and controls, and correlated these to symptom severity. The UHR group as a whole did not differ significantly from controls. AMPT significantly reduced symptom severity in the UHR group (p=0.014). Higher synaptic dopamine concentration predicted larger reduction of positive symptoms following depletion in the UHR group (p=0.01). In UHR patients, positive symptoms responded to dopamine depletion, comparable to observations in schizophrenia, suggesting a similar mechanism. Higher synaptic dopamine concentration was associated with more severe positive symptoms and a greater reduction of these symptoms following depletion.

Pre-pulse inhibition and striatal dopamine in subjects at an ultra-high risk for psychosis

Reduced prepulse inhibition (PPI) of the acoustic startle response is thought to represent a robust biomarker in schizophrenia. Reduced PPI has been demonstrated in subjects at ultra high risk (UHR) for developing psychosis. Imaging studies report disruption of striatal dopaminergic neurotransmission in patients with schizophrenia. First, we compared the PPI of the acoustic startle response in UHR subjects versus healthy controls, to see if we could replicate previous findings of reduced PPI; secondly, we investigated our hypothesis that PPI would be negatively correlated with striatal synaptic dopamine (DA) concentration. We measured the startle reactivity and PPI of the acoustic startle response in 14 UHR subjects, and 14 age- and gender-matched healthy controls. Imaging of 11 UHR subjects and 11 healthy controls was completed by an [123I]-IBZM (radiotracer for dopamine D2/3 receptors) SPECT, at baseline and again after DA depletion with alpha-methyl-para-tyrosine (AMPT). The percentage change in striatal [123I]-IBZM radiotracer binding potential is a proxy of striatal synaptic DA concentration. UHR subjects showed reduced PPI, compared to control subjects. In both UHR and control subjects, there were no significant correlations between striatal synaptic DA concentration and PPI. We provide further evidence for the hypothesis that these two biomarkers are measuring different aspects of pathophysiology.

Startle reactivity and prepulse inhibition of the acoustic startle response are modulated by catechol-O-methyl-transferase Val158 Met polymorphism in adults with 22q11 deletion syndrome

22q11 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22, which includes the gene coding for catechol-O-methyl-transferase (COMT). High dopamine (DA) levels due to COMT haplo-insufficiency may be associated with the increased risk of developing schizophrenia in adults with 22q11DS. Reduced prepulse inhibition (PPI) of the acoustic startle response has been associated with schizophrenia and with disrupted DAergic transmission in the prefrontal cortex (PFC). COMT Val158Met polymorphism has been shown to influence PPI. We report the first study in adults with 22q11DS to examine PPI of the acoustic startle response and its modulation by COMT Val158Met polymorphism. Startle reactivity (SR) and PPI of the acoustic startle response were measured in 23 adults with 22q11DS and 21 healthy controls. 22q11DS subjects were genotyped for the functional COMT Val158Met polymorphism. 22q11DS Met hemizygotes showed reduced SR and PPI compared with 22q11DS Val hemizygotes. The effect of COMT Val158Met polymorphism on PPI was no longer significant when controlling for baseline SR. Met hemizygosity in 22q11DS is associated with reduced SR and influences PPI indirectly. Decreased PFC functioning following excessive PFC DA levels may be one of the mechanisms by which the Met genotype in 22q11DS disrupts SR.

Cortical Morphology Differences in Subjects at Increased Vulnerability for Developing a Psychotic Disorder: A Comparison between Subjects with Ultra-High Risk and 22q11.2 Deletion Syndrome

Introduction Subjects with 22q11.2 deletion syndrome (22q11DS) and subjects with ultra-high risk for psychosis (UHR) share a risk of approximately 30% to develop a psychotic disorder. Studying these groups helps identify biological markers of pathophysiological processes involved in the development of psychosis. Total cortical surface area (cSA), total cortical grey matter volume (cGMV), cortical thickness (CT), and local gyrification index (LGI) of the cortical structure have a distinct neurodevelopmental origin making them important target markers to study in relation to the development of psychosis. Materials and Methods Structural T1-weighted high resolution images were acquired using a 3 Tesla Intera MRI system in 18 UHR subjects, 18 22q11DS subjects, and 24 matched healthy control (HC) subjects. Total cSA, total cGMV, mean CT, and regional vertex-wise differences in CT and LGI were assessed using FreeSurfer software. The Positive and Negative Syndrome Scale was used to assess psychotic symptom severity in UHR and 22q11DS subjects at time of scanning. Results 22q11DS subjects had lower total cSA and total cGMV compared to UHR and HC subjects. The 22q11DS subjects showed bilateral lower LGI in the i) prefrontal cortex, ii) precuneus, iii) precentral gyrus and iv) cuneus compared to UHR subjects. Additionally, lower LGI was found in the left i) fusiform gyrus and right i) pars opercularis, ii) superior, and iii) inferior temporal gyrus in 22q11DS subjects compared to HC. In comparison to 22q11DS subjects, the UHR subjects had lower CT of the insula. For both risk groups, positive symptom severity was negatively correlated to rostral middle frontal gyrus CT. Conclusion A shared negative correlation between positive symptom severity and rostral middle frontal gyrus CT in UHR and 22q11DS may be related to their increased vulnerability to develop a psychotic disorder. 22q11DS subjects were characterised by widespread lower degree of cortical gyrification linked to early and postnatal neurodevelopmental pathology. No implications for early neurodevelopmental pathology were found for the UHR subjects, although they did have distinctively lower insula CT which may have arisen from defective pruning processes during adolescence. Implications of these findings in relation to development of psychotic disorders are in need of further investigation in longitudinal studies.

Dopamine in high-risk populations: A comparison of subjects with 22q11.2 deletion syndrome and subjects at ultra high-risk for psychosis

Striatal dopamine (DA) dysfunction has been consistently reported in psychotic disorders. Differences and similarities in the pathogenesis between populations at clinical and genetic risk for developing psychosis are yet to be established. Here we explored markers of dopamine (DA) function in subjects meeting clinically ultra-high risk criteria for psychosis (UHR) and in subjects with 22q11.2 deletion syndrome (22q11DS), a genetic condition associated with significant risk for developing psychotic disorders. Single Photon Emission Computed Tomography (SPECT) with 123I-labelled iodobenzamide ([123I]IBZM) was used to measure striatal DA D2/3 receptor binding potential (D2R BPND). Also, peripheral DAergic markers were assessed in serum and urine (plasma prolactin (pPRL), plasma homovanillic acid (pHVA) and urine DA(uDA)). No significant difference in striatal D2R BPND was found between UHR and 22q11DS subjects. Compared to UHR subjects, pPRL and pHVA were lower and uDA levels were higher in the 22q11DS subjects. However, after correcting for age and gender, only pPRL as significantly lower in the 22q11DS patients. These results may suggest that there are differences in DAergic markers between subjects with UHR and with 22q11DS that may reflect differences in the pathways to psychosis. However, bigger samples are needed to replicate these findings.

The impact of affective symptoms on personal recovery of patients with severe mental illness

Background: Clinical recovery is often defined as remission of symptoms. Personal recovery is described as growing beyond the catastrophic effects of mental illness, sometimes despite ongoing symptoms. Aims: To examine the relationship between the severity of clinical symptom domains and personal recovery in patients with severe mental illness (SMI). Methods: Symptom severity and personal recovery of 105 outpatients with SMI at Mentrum, part of Arkin Institute for Mental Health in Amsterdam, the Netherlands, were assessed using the Brief Psychiatric Rating Scale–Expanded Version (BPRS-E) and the Mental Health Recovery Measure (MHRM). Correlation and regression analyses were used to investigate the associations. Results: The multiple regression analysis showed that only affective symptoms significantly predicted personal recovery, whereas neither positive nor negative symptom severity added to the explained variance in the model. Conclusion: The association between affective symptoms and personal recovery in patients with SMI implies that treatment of affective symptoms may advance personal recovery, and/or support of personal recovery may improve mood, whereas focussing on treatment of psychotic symptoms might not be the key to personal recovery. More research is needed to elucidate causal interrelations.