D. H. Nieman

White-matter markers for psychosis in a prospective ultra-high-risk cohort

BACKGROUNDnSubjects at ultra high risk (UHR) for developing psychosis have differences in white matter (WM) compared with healthy controls. WM integrity has not yet been investigated in UHR subjects in relation to the development of subsequent psychosis. Hence, we investigated a prospective cohort of UHR subjects comparing whole brain fractional anisotropy (FA) of those later developing psychosis (UHR-P) to those who did not (UHR-NP).nnnMETHODnWe recruited 37 subjects fulfilling UHR criteria and 10 healthy controls. Baseline 3 Tesla magnetic resonance imaging (MRI) scans and Positive and Negative Syndrome Scale (PANSS) ratings were obtained. UHR subjects were assessed at 9, 18 and 24 months for development of frank psychosis. We compared baseline FA of UHR-P to controls and UHR-NP subjects. Furthermore, we related clinical data to MRI outcome in the patient population.nnnRESULTSnOf the 37 UHR subjects, 10 had transition to psychosis. UHR-P subjects showed significantly lower FA values than control subjects in medial frontal lobes bilaterally. UHR-P subjects had lower FA values than UHR-NP subjects, lateral to the right putamen and in the left superior temporal lobe. UHR-P subjects showed higher FA values, compared with UHR-NP, in the left medial temporal lobe. In UHR-P, positive PANSS negatively correlated to FA in the left middle temporal lobe. In the total UHR group positive PANSS negatively correlated to FA in the right superior temporal lobe.nnnCONCLUSIONSnUHR subjects who later develop psychosis have differences in WM integrity, compared with UHR subjects who do not develop psychosis and to healthy controls, in brain areas associated with schizophrenia.

Neurocognitive functioning before and after the first psychotic episode: does psychosis result in cognitive deterioration?

BACKGROUNDnCognitive impairment is considered to be a core characteristic of schizophrenia. The relationship between psychosis and cognitive deterioration, however, remains unclear. This longitudinal study investigated the neuropsychological functioning of patients before and after their first psychotic episode. Cognitive functioning of participants who later developed a psychosis was compared to that of people at ultra-high risk (UHR) for psychosis who did not develop psychosis at follow-up and healthy controls.MethodParticipants were 41 persons at UHR for psychosis (the UHR group), of whom 17 developed psychosis between the first and second assessment. Seventeen healthy controls were included in the study. Cognitive performance was assessed at intake (T0) and again after 18 months (T1). The areas of cognitive functioning assessed include verbal memory and learning, visuospatial working memory, executive function, sustained attention and motor speed.nnnRESULTSnThe transition group did not perform significantly worse at the second assessment than at the first on any of the outcome measures. The UHR group performed better on a verbal learning and memory test at T1 compared to T0. At T0, the control group scored significantly better than the UHR group and the transition group on the verbal learning and memory test and the verbal fluency test.nnnCONCLUSIONSnThe results indicate that no cognitive deterioration occurs during the first psychotic episode. Problems in verbal memory may be present before the first episode of psychosis.

Early intervention in patients at ultra high risk of psychosis: benefits and risks

Objective:u2002 Prediction of transition to psychosis in the prodromal phase of schizophrenia has raised interest in intervention prior to the onset of frank psychosis. The aim of this review was to examine whether interventions in the prodromal phase have a favourable benefit/risk ratio.

Three-year course of clinical symptomatology in young people at ultra high risk for transition to psychosis

Velthorst E, Nieman DH, Klaassen RMC, Becker HE, Dingemans PM, Linszen DH, de Haan L. Three year course of clinical symptomatology in young people at ultra high risk for transition to psychosis.

Adapted cognitive–behavioural therapy required for targeting negative symptoms in schizophrenia: meta-analysis and meta-regression

BACKGROUNDnThere is an increasing interest in cognitive-behavioural therapy (CBT) interventions targeting negative symptoms in schizophrenia. To date, CBT trials primarily focused on positive symptoms and investigated change in negative symptoms only as a secondary outcome. To enhance insight into factors contributing to improvement of negative symptoms, and to identify subgroups of patients that may benefit most from CBT directed at ameliorating negative symptoms, we reviewed all available evidence on these outcomes.nnnMETHODnA systematic search of the literature was conducted in PsychInfo, PubMed and the Cochrane register to identify randomized controlled trials reporting on the impact of CBT interventions on negative symptoms in schizophrenia. Random-effects meta-analyses were performed on end-of-treatment, short-term and long-term changes in negative symptoms.nnnRESULTSnA total of 35 publications covering 30 trials in 2312 patients, published between 1993 and 2013, were included. Our results showed studies pooled effect on symptom alleviation to be small [Hedges g = 0.093, 95% confidence interval (CI) -0.028 to 0.214, p = 0.130] and heterogeneous (Q = 73.067, degrees of freedom = 29, p < 0.001, τ 2 = 0.081, I 2 = 60.31) in studies with negative symptoms as a secondary outcome. Similar results were found for studies focused on negative symptom reduction (Hedges g = 0.157, 95% CI -0.10 to 0.409, p = 0.225). Meta-regression revealed that stronger treatment effects were associated with earlier year of publication, lower study quality and with CBT provided individually (as compared with group-based).nnnCONCLUSIONSnThe co-occurring beneficial effect of conventional CBT on negative symptoms found in older studies was not supported by more recent studies. It is now necessary to further disentangle effective treatment ingredients of older studies in order to guide the development of future CBT interventions aimed at negative symptom reduction.

Ethnicity and baseline symptomatology in patients with an At Risk Mental State for psychosis

BACKGROUNDnEthnicity has been associated with different incidence rates and different symptom profiles in young patients with psychotic-like disorders. No studies so far have examined the effect of ethnicity on symptoms in people with an At Risk Mental State (ARMS).nnnMETHODnIn this cross-sectional study, we analysed the relationship between ethnicity and baseline data on the severity of psychopathology scores in 201 help-seeking patients who met the ARMS criteria and agreed to participate in the Dutch Early Detection and Intervention (EDIE-NL) trial. Eighty-seven of these patients had a non-Dutch ethnicity. We explored the possible mediating role of ethnic identity.nnnRESULTSnHigher rates of negative symptoms, and of anhedonia in particular, were found in the ethnic minority group. This result could be attributed mainly to the Moroccan-Dutch and Turkish-Dutch subgroups, who also presented with more depression symptoms when the groups were examined separately. The ethnic minority group displayed a lower level of ethnic group identity compared to the immigrants of the International Comparative Study of Ethnocultural Youth (ICSEY). Ethnic identity was inversely related to symptoms in the Moroccan-Dutch patient group.nnnCONCLUSIONSnThe prevalence of more severe negative symptoms and depression symptoms in ethnic minority groups deserves more attention, as the experience of attenuated positive symptoms when accompanied by negative symptoms or distress has proven to be predictive for transition to a first psychotic episode.

Cerebral dopamine deficiency, plasma monoamine alterations and neurocognitive deficits in adults with phenylketonuria

BACKGROUNDnPhenylketonuria (PKU), a genetic metabolic disorder that is characterized by the inability to convert phenylalanine to tyrosine, leads to severe intellectual disability and other cerebral complications if left untreated. Dietary treatment, initiated soon after birth, prevents most brain-related complications. A leading hypothesis postulates that a shortage of brain monoamines may be associated with neurocognitive deficits that are observable even in early-treated PKU. However, there is a paucity of evidence as yet for this hypothesis.nnnMETHODSnWe therefore assessed in vivo striatal dopamine D2/3 receptor (D2/3R) availability and plasma monoamine metabolite levels together with measures of impulsivity and executive functioning in 18 adults with PKU and average intellect (31.2 ± 7.4 years, nine females), most of whom were early and continuously treated. Comparison data from 12 healthy controls that did not differ in gender and age were available.nnnRESULTSnMean D2/3R availability was significantly higher (13%; p = 0.032) in the PKU group (n = 15) than in the controls, which may reflect reduced synaptic brain dopamine levels in PKU. The PKU group had lower plasma levels of homovanillic acid (p < 0.001) and 3-methoxy-4-hydroxy-phenylglycol (p < 0.0001), the predominant metabolites of dopamine and norepinephrine, respectively. Self-reported impulsivity levels were significantly higher in the PKU group compared with healthy controls (p = 0.033). Within the PKU group, D2/3R availability showed a positive correlation with both impulsivity (r = 0.72, p = 0.003) and the error rate during a cognitive flexibility task (r = 0.59, p = 0.020).nnnCONCLUSIONSnThese findings provide further support for the hypothesis that executive functioning deficits in treated adult PKU may be associated with cerebral dopamine deficiency.

Treating prolactinoma and psychosis: medication and cognitive behavioural therapy

The patient in this case report had two severe medical conditions that require oppositional treatment: prolactinoma and psychosis. A prolactinoma is a benign tumour of the pituitary gland that produces prolactin. Dopamine agonist medication is the first-line treatment in patients with prolactinoma. The psychotic symptoms started after a dosage increase of a dopamine D2-receptor agonist. Several antipsychotic medications were tried with and without the dopamine D2-receptor agonist, but severe command hallucinations remained. Cognitive behavioural therapy (CBT) was added which reduced the impact of the hallucinations to a great extent, indicating that CBT can have an additional positive effect in prolactinoma patients with psychosis that shows incomplete recovery after antipsychotic medication. Future research should be aimed at the severe and prolonged side effects of dopamine agonists in the treatment of prolactinoma patients with multiple risk factors for a psychotic decompensation.

Psycho-education on extra-ordinary experiences and risky thinking styles for people with an At Risk Mental State

Since the early days of schizophrenia research, hyper-responsivity within the dopamine system was believed to underlie the positive symptoms of this disorder; however, the source of this disruption has been unknown. However, recent studies from human schizophrenia patents suggest that hyperactivity within the hippocampal formation may drive this psychosis. In a rodent developmental disruption model of schizophrenia, we found that the ventral subiculum of the hippocampus is hyperactive secondary to a loss of GABAergic interneuron markers. Moreover, we found that activity within the ventral subiculum drives tonic dopamine neuron firing, thereby controlling the “gain” of the phasic dopamine response to stimuli. Inactivation of the ventral subiculum in the rodent model was found to reverse the dopamine system overdrive and the behavioral hyper-responsivity to amphetamine, providing an important link between the hippocampus and dopamine system regulation. The ventral subiculum is also recognized as a central mediator of the stress response, and receives potent drive from stress-related areas such as the noradrenergic system and the amygdala. Given the high sensitivity of hippocampal neurons to stress-induced damage, these data suggest that stress may be a precipitating factor in schizophrenia onset via disruption of hippocampal interneuron function. We propose that the resultant loss of interneuron gating within the hippocampus leads to a condition whereby there is an inappropriate assignment of context, leading the individual to interpret all stimuli as being highly salient. Moreover, the transition to schizophrenia may be circumvented by treating the maladaptive responses to stressors during the premorbid state that contribute to hippocampal dysfunction. Plenary Lecture I

NEURAPRO: a multi-centre RCT of omega-3 polyunsaturated fatty acids versus placebo in young people at ultra-high risk of psychotic disorders—medium-term follow-up and clinical course

This study reports a medium-term follow-up of a randomised, double-blind, placebo-controlled trial of omega-3 polyunsaturated fatty acids (PUFA) in ultra-high risk for psychosis (UHR) patients. Primary outcomes of interest were transition to psychosis and symptomatic and functional outcome. A secondary aim was to investigate clinical predictors of medium-term outcome. Three hundred four UHR participants were recruited across 10 specialised early psychosis services in Australia, Asia, and Europe. The intervention consisted of 1.4u2009g/daily of omega-3 PUFA or placebo, plus up to 20 sessions of cognitive-behavioural case management (CBCM), over the 6-month study period, with participants receiving further CBCM sessions on basis of need between months 6–12. Mean time to follow-up was 3.4 (medianu2009=u20093.3; SDu2009=u20090.9) years. There was a modest increase in transitions between 12-month and medium-term follow-up (11–13%) and substantial improvement in symptoms and functioning between baseline and follow-up, with no differences between the treatment groups. Most improvement had been achieved by end of the intervention. 55% of the sample received mental health treatment between end of intervention and follow-up. Omega-3 PUFA did not provide additional benefits to good quality psychosocial intervention over the medium term. Although most improvement had been achieved by end of intervention the substantial rates of post-intervention mental health service use indicate longer-term clinical need in UHR patients. The post-intervention phase treatment or the longer-term effect of CBCM, or a combination of the two, may have contributed to maintaining the gains achieved during the intervention phase and prevented significant deterioration after this time.Omega-3: No benefit to those at risk of psychosisOmega-3 fatty acids, when given alongside traditional therapies, provide no extra benefits to patients at high risk of developing psychosis. In attempts to validate a previous clinical trial wherein omega-3 reduced the risk of ultra-high-risk patients transitioning to psychosis, Patrick McGorry, of the National Centre of Excellence in Youth Mental Health, Australia, and his team looked to replicate the findings in a larger cohort. Despite improvements in symptoms seen in a medium-term follow-up of 304 patients after ~3.4 years, no extra benefit or reduced transitioning was seen in those additionally receiving omega-3 fatty acids. The bulk of treatment benefit was seen between 0–12 months, but the data indicate a clear need for ongoing patient care. This study also revealed psychopathology score level, anxiety, and societal functioning to be strong indicators of psychosis transition risk.