Is early intervention for psychosis feasible and effective?

Services that provide comprehensive, early intervention (EI) have shown promise in improving long-term outcomes in schizophrenia. This article reviews the rationale and salient concepts relevant to understanding the growing EI literature. A selective review of studies evaluating the effectiveness of integrated EI is followed by a discussion of feasibility, especially in the US context. Finally, the authors present a framework that seeks to integrate activities traditionally categorized and separated as discovery and implementation. This framework is offered as a way to advance both goals.     

Left temporal rhythmic electrical activity: a correlate for psychosis? A case report

Summary. It is well recognized that epileptic patients are at higher risk for acute or chronic psychotic states than non-epileptic subjects. Here we present intracranial depth electrode recordings during a psychotic episode in a 20-year-old woman who was referred for presurgical evaluation. Unrelated to her seizures, she presented acoustic hallucinations and delusions and became agitated for a duration of 18–24 hours. During this period, a new unusual pattern of sharp slow waves was seen semi-rhythmically every 2–3sec from left anterior neocortical temporal areas. Her condition responded well to a treatment with Haloperidol, but not with Benzodiazepines. Ictal and interictal scalp- and depth-EEG recordings outside the psychotic episode as well as MRI-based volumetry, PET, SPECT and neuropsychological testing gave evidence of bilateral temporal and frontal dysfunction. This case report suggests that psychosis in epileptic patients may be based on a bilateral cerebral dysfunction linked together in a pathological network, but with a focal (here: left temporal) driving mechanism. Received August 6, 1998; accepted February 3, 1999     

A 1H-MRS investigation of the medial temporal lobe in antipsychotic-naïve and early-treated first episode psychosis

Schizophrenia is associated with significant brain abnormalities, including changes in brain metabolites as measured by proton magnetic resonance spectroscopy (MRS). What remains unclear is the extent to which these changes are a consequence of the emergence of psychotic disorders or the result of treatment with antipsychotic medication. We assessed 34 patients with first episode psychosis (15 antipsychotic na?ve) and 19 age- and gender-matched controls using short-echo MRS in the medial temporal lobe bilaterally. Overall, there were no differences in any metabolite, regardless of treatment status. However, when the analysis was limited to patients with a diagnosis of schizophrenia, schizophreniform or schizoaffective disorder, significant elevations of creatine/phosphocreatine (Cr/PCr) and myo-inositol (mI) were found in the treated group. These data indicate a relative absence of temporal lobe metabolic abnormalities in first episode psychosis, but suggest that some treatment-related changes in mI might be apparent in patients with schizophrenia-spectrum diagnoses. Seemingly illness-related Cr/PCr elevations were also specific to the diagnosis of schizophrenia-spectrum disorder and seem worthy of future study.     

Does early postoperative drug regimen impact seizure control in patients undergoing temporal lobe resections?

Objective

To evaluate the impact of postoperative antiepileptic drug (AED) load on seizure control in patients who underwent surgical treatment for pharmacoresistant mesiotemporal lobe epilepsy during the first two postoperative years.

Patients and methods

532 consecutive patients (48.7% males and 51.7% females) who underwent surgical treatment for mesiotemporal lobe epilepsy were retrospectively evaluated regarding effects of AED load on seizures control during the first 2 years following epilepsy surgery. We analyzed whether postoperative increases in postoperative AED load are associated with better seizure control in patients initially not seizure free, and if postoperative decreases in postoperative AED load would increase the risk for seizure persistence or recurrence. For statistical analyses, Fisher’s exact and Wilcoxon test were applied.

Results

68.9, 64.0 and 59.1% of patients were completely seizure free (Engel Ia) at 3, 12 and 24 months after surgery, respectively. Patients in whom daily drug doses were increased did not have a higher rate of seizure freedom at any of the three follow-up periods. Of 16 patients achieving secondary seizure control at 12 months after surgery, only one did so with an increase in drug load in contrast to 15 patients who experienced a running down of seizures independent of drug load increases. Decreases in drug load did not significantly increase the risk for seizure recurrence. Of postoperatively seizure free patients at 3 months after surgery in whom AED were consequently reduced, 85% remained completely seizure free at 1 year and 76% at 1 year after surgery, respectively, as opposed to 86% each when AED was not reduced (differences n.s.). Mean daily drug load was significantly lower in seizure free patients at 12 and 24 months compared to patients with ongoing seizures.

Conclusion

In this large patient cohort stratified to the epilepsy syndrome neither did a postoperative reduction in drug load significantly increase the risk for seizure relapse nor did increases in drug dosages lead to improved seizure control. Mean drug load was on average lower in seizure free- than non-seizure free patients at 12 and 24 months of follow-up. Secondary seizure control after initial postoperative seizures in > 90% of cases occurred as a running down, independent of an AED increase. Thus, the effect of the surgical intervention rather than the postoperative drug regimen was the key determinant for seizure control. This finding supports a curative role of temporal lobe surgery rather than an effect rendering the majority of patients’ pharmacoresponsive with a critical role of the antiepileptic drug regime for seizure control.

     

Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction

The insular cortex is one of the brain regions that show consistent abnormalities in both structural and functional neuroimaging studies of schizophrenia. In healthy individuals, the insula has been implicated in a myriad of physiologic functions. The anterior cingulate cortex (ACC) and insula together constitute the salience network, an intrinsic large-scale network showing strong functional connectivity. Considering the insula as a functional unit along with the ACC provides an integrated understanding of the role of the insula in information processing. In this review, we bring together evidence from imaging studies to understand the role of the salience network in schizophrenia and propose a model of insular dysfunction in psychosis.     

Epilepsy-related psychosis: A role for autoimmunity?

Postictal psychosis (PIP) is a serious psychiatric complication of epilepsy that occurs in approximately 6% of patients following multiple complex partial or generalized seizures. The psychosis is classically described as having a pleomorphic phenomenology, including paranoid, grandiose, and religious delusions as well as multimodal hallucinations with prominent affective changes and agitation. Little is understood about the pathophysiology of the condition.There has been a recent increase in interest in the relevance of autoimmunity to the pathogenesis of both epilepsy and psychosis. Studies have demonstrated the presence of antibodies directed against synaptic autoantigens (such as the N-methyl-d-aspartate receptor or the voltage-gated potassium channel complex) in approximately 10% of cases of sporadic epilepsy. These same autoantibodies are known to cause encephalopathy syndromes which feature psychiatric symptoms, usually psychosis, as a prominent part of the phenotype as well as other neurological features such as seizures, movement disorders, and autonomic dysfunction. It is beginning to be asked if these antibodies can be associated with a purely psychiatric phenotype.Here, we hypothesize that PIP may be an autoimmune phenomenon mediated by autoantibodies against synaptic antigens. More specifically, we outline a potential mechanism whereby long or repeated seizures cause short-lived blood–brain barrier (BBB) dysfunction during which the brain becomes exposed to pathogenic autoantibodies. In essence, we propose that PIP is a time-limited, seizure-dependent, autoantibody-mediated encephalopathy syndrome. We highlight a number of features of PIP that may be explained by this mechanism, such as the lucid interval between seizures and onset of psychosis and the progression in some cases to a chronic, interictal psychosis.     

Does giving up substance use work for patients with psychosis? A systematic meta-analysis

Objective: To assess the extent to which ceasing the use of cannabis or other substances reduces the symptoms and social disability associated with psychotic illness. Methods: The electronic databases CINAHL, EMBASE, MEDLINE and PsycINFO were searched for peer-reviewed publications in English that report data about the characteristics of current and former substance-using patients diagnosed with psychotic illnesses. The searches yielded 328 articles, of which 23 studies met the inclusion criteria. Four key outcome variables; positive symptoms, negative symptoms, ratings of depression and global function, and five other measures of outcome that were reported in five or more studies were examined using meta-analysis. Results: Current substance-using patients were significantly younger than former substance-using patients (standardised mean difference (SMD) = -0.38), but did not differ in age at onset of psychosis, sex, level of education or marital status. Current substance users had higher scores on rating scales of positive symptoms (SMD = 0.29) and depression (SMD = 0.36), and lower scores on global function (SMD = -0.26) when compared with former substance users. There was a significant improvement in the ratings of positive symptoms, mood and global function among patients who stopped using substances during the first episode of psychosis, while improvements in the symptoms of patients with a more established psychotic illness did not reach statistical significance. Conclusion: The results suggest that substance use contributes to both the symptoms and the burden of disability experienced by patients with psychosis. Patients in the early stages of psychotic illness should be informed about the benefits of giving up substances earlier, rather than later in the illness. Psychiatric services should regard the treatment of substance use as an integral part of the treatment of psychotic disorders.     

Does hippocampal FDG-PET asymmetry predict verbal memory dysfunction after left temporal lobectomy?

The primary aim of this study was to determine whether hippocampal asymmetries in fluorodeoxyglucose (FDG) uptake on preoperative PET scans would predict post-temporal lobectomy verbal memory (VM) decline in patients with left temporal lobe epilepsy. A quantitative asymmetry index (AI) of uptake values within a hippocampal region of interest (ROI) was defined by an automated technique. No statistically significant effect of the hippocampal AI on the outcome measure, the pre- to postsurgical change in Logical Memory Percent Retention, was evident. Post hoc analyses revealed that AIs of the superior and inferior temporal gyri approached significance, however, with relatively greater left-sided preoperative metabolism predicting better VM outcomes. This finding suggests reorganization of function and/or retained function of remaining tissue. Although hippocampal FDG-PET asymmetries did not significantly predict changes in VM, the predictive value of neocortical AIs should be further explored. Automated ROI parcellation provides a feasible tool for use in such investigations.     

Does treatment delay predict occupational functioning in first-episode psychosis?

Although duration of untreated psychosis (DUP) predicts treatment outcome as assessed by symptoms in first-episode psychosis, there is much less evidence concerning its relation to social functioning. We present the results of a prospective study of 163 first-episode psychosis patients examining occupational activity at three years, after initiation of treatment. Both shorter DUP and higher social support were significantly associated with more full time occupational activity at follow-up. The findings suggest the importance of reducing treatment delay and increasing social support in order to improve occupational outcomes for those with first-episode psychosis.     

Does apolipoprotein A1 predict microstructural changes in subgenual cingulum in early Parkinson?

Higher plasma cholesterol levels are associated with lower Parkinson’s disease (PD) risk. Apolipoprotein A-1 (ApoA-1) is a surface marker of brain HDL-like particles associated with the time of PD onset. Clinical correlates of serum Apolipoprotein A1 levels with structural brain connectivity in PD-related disorders remains unclear. Here, we applied a novel diffusion-weighted imaging approach [Diffusion Magnetic Resonance Imaging (MRI) Connectometry] to explore the association between ApoA-1 and structural brain connectivity in PD. Participants involved in this research were recruited from Parkinson’s Progression Markers Initiative (PPMI). Diffusion MRI connectometry was conducted using a multiple regression against apoA-1 for 36 patients with DTI measurements available in the baseline visit. Fiber results of the connectometry were then reconstructed for each patient, and diffusion parameters were extracted and regressed against apoA-1 levels. Connectometry results revealed the subgenual cingulum to be associated with ApoA-1, with different FDR yields. This result was further supported by significant negative correlation of Quantitative Anisotropic (QA) of left subgenual cingulum (Pearson’s coefficient = ?0.398, p = 0.020) and Generalized Fractional Anisotropic (GFA) of right subgenual cingulum (Pearson’s coefficient ?0.457, p = 0.007) with plasma apoA-1 levels, in a multiple regression model with age and sex. The subgenual cingulum encompasses fibers from the anterior cingulate cortex and anterior thalamus. These structures are involved in PD-associated psychosis and executive cognitive decline. We demonstrated for the first time that apoA-1, as a blood marker, can predict microstructural changes in white matter regions in PD patients with undisturbed cognition and mild motor disability.     

Does electroencephalogram phase variability account for reduced P3 brain potential in externalizing disorders?

Objective

Amplitude deficits of the P3 event-related potential (ERP) are associated with externalizing psychopathology but little is known about the nature of underlying brain electrical activity that accounts for this amplitude reduction. We sought to understand if group differences in task-induced phase-locking in electroencephalographic (EEG) delta and theta frequencies may account for P3-externalizing associations.

Methods

Adult males (N = 410) completed a visual oddball task and frontal and parietal P3-related delta- and theta-band phase-invariant evoked energy and inter-trial phase-locking measures were investigated with respect to the externalizing spectrum, including substance dependence, adult antisociality, and childhood disruptive disorders. We hypothesized that P3-related phase-locking is weaker in externalizing-diagnosed individuals and this might mediate prior findings of reduced evoked P3 energy.

Results

Reductions in both evoked energy and phase-locking, in both frequency bands, at both scalp sites, were associated with greater odds of externalizing diagnoses. Generally, adding phase-locking to evoked energy came with better prediction model fit. Moreover, reduced theta-band phase-locking partially mediated the effects of within-frequency evoked energy on externalizing prediction.

Conclusions

Inter-trial phase-locking underlying P3 appears to be an important distinction between externalizing and control subjects.

Significance

This cross-trial phase-variability for externalizing-diagnosed individuals might reflect deficient top-down “tuning” by neuromodulatory systems.     

Exploring neural dysfunction in ‘clinical high risk’ for psychosis: A quantitative review of fMRI studies

Individuals at clinical high risk (CHR) of developing psychosis present with widespread functional abnormalities in the brain. Cognitive deficits, including working memory (WM) problems, as commonly elicited by n-back tasks, are observed in CHR individuals. However, functional MRI (fMRI) studies, comprising a heterogeneous cluster of general and social cognition paradigms, have not necessarily demonstrated consistent and conclusive results in this population. Hence, a comprehensive review of fMRI studies, spanning almost one decade, was carried out to observe for general trends with respect to brain regions and cognitive systems most likely to be dysfunctional in CHR individuals. 32 studies were included for this review, out of which 22 met the criteria for quantitative analysis using activation likelihood estimation (ALE). Task related contrast activations were firstly analysed by comparing CHR and healthy control participants in the total pooled sample, followed by a comparison of general cognitive function studies (excluding social cognition paradigms), and finally by only looking at n-back working memory task based studies. Findings from the ALE implicated four key dysfunctional and distinct neural regions in the CHR group, namely the right inferior parietal lobule (rIPL), the left medial frontal gyrus (lmFG), the left superior temporal gyrus (lSTG) and the right fronto-polar cortex (rFPC) of the superior frontal gyrus (SFG). Narrowing down to relatively few significant dysfunctional neural regions is a step forward in reducing the apparent ambiguity of overall findings, which would help to target specific neural regions and pathways of interest for future research in CHR populations.     

Baby or bathwater? Referrals of “non-cases” in a targeted early identification intervention for psychosis

Purpose

To explore the unintended impact of a targeted case identification (TCI) campaign for first episode psychosis (FEP) on people not experiencing FEP (“non-cases”) with respect to referral patterns and reasons for being a non-case.

Methods

Sources of referral, reasons for being a non-case, and subsequent referral destinations of non-cases were examined before and after a TCI.

Results

Following the TCI, a greater proportion of non-cases lived outside the study catchment area. A smaller proportion was referred by the parent hospital’s emergency room or had a substance-induced psychosis.

Conclusions

TCIs for FEP may have unintended effects, with implications for early case identification and early intervention services.

     

Does the duration of untreated psychosis affect prognosis in schizophrenia?

Clinical Dilemma: 'An 18-year-old patient, who has been suffering from a prolonged psychotic state, is hospitalized for the first time in his life in our department. We diagnose his condition as schizophrenia, and start anti-psychotic medication and supportive psychotherapy. His parents join the psycho-educational group for families in our department. After one of the group sessions, his parents worriedly approach us with the question whether the fact that their son had been psychotic and had not received anti-psychotic medications for many months before his hospitalization predicts a bad prognosis for his disease course and outcome. Does the duration of untreated psychosis (DUP) affect prognosis in schizophrenia?'     

Autonomic dysfunction in PD: a window to early detection?

It has been suggested that autonomic dysfunction constitutes a biomarker for early detection of the disease process in Parkinson disease (PD). Recent findings based on cardiac sympathetic and striatal dopaminergic imaging in the same patients indicate that this view is overly simple. Although evidence of cardiac sympathetic denervation is associated with other non-motor manifestations such as anosmia, REM behavior disorder, dementia, baroreflex failure, and orthostatic hypotension (OH), across individual patients the severities of OH and of the cardiac sympathetic lesion (indicated by thoracic 6-[(18)F]fluorodopamine PET scanning) are unrelated to the severity of the putamen dopaminergic lesion (indicated by brain 6-[(18)F]fluorodopa PET scanning). Moreover, whereas cases have been reported with neuroimaging evidence of cardiac sympathetic denervation several years before motor onset of PD, in other cases loss of cardiac sympathetic innervation progresses approximately concurrently with the movement disorder or can even occur as a late finding. Bases for independent sympathetic noradrenergic and striatal dopaminergic lesions in Lewy body diseases remain poorly understood. In elderly patients with unexplained OH or other evidence of autonomic failure, it is reasonable for clinicians to look for subtle signs of parkinsonism, such as masked facies, cogwheel rigidity, and shuffling gate.