Verbal memory improvement in first-episode psychosis APOE-ε4 carriers: a pleiotropic effect?

Background: Verbal memory impairment is a core feature in schizophrenia even at early stages of the disease, but its etiopathogenesis is not fully understood. The APOE-ε4 is the main genetic risk factor for late-onset Alzheimer's disease. Our primary goal was to ascertain whether APOE-ε4 status had a pleiotropic effect in early stages of the illness. Participants and methods: A total of 86 first-episode psychosis (FEP) outpatients and 39 healthy volunteers were recruited. Demographic and clinical data, APOE genotyping, and a neuropsychological test battery including the California Verbal Learning Test - second edition (CVLT-II) were administered and assessed at study entry and at 1-year follow-up. Data were analyzed using mixed-model repeated measures, where the dependent variable was verbal memory indexed by California Verbal Learning Test (CVLT) Trials 1-5 total recall score. Results: FEP-APOE-ε4 carriers and FEP-APOE-ε4 noncarriers had similar symptom severity, clinical outcomes, premorbid and current intelligence quotient, and exposure to antipsychotics. There was a main effect of group on CVLT 1-5 (FEP =43.30 vs control =58.25; F[1, 119.7]=42.97; P<0.001) as well as an APOE-ε4 by group by time (F[4, 116.2]=2.73, P=0.033) interaction with only FEP-APOE-ε4 carriers showing improved verbal memory at follow-up. Conclusion: Our study is the first to report improvement in verbal memory in persons afflicted by FEP who are APOE-ε4 carriers and replicates the prominent verbal memory deficits present in FEP. Our work provides further evidence pointing to an antagonistic pleiotropic effect of APOE-ε4 in neuropsychiatric disorders. Our results merit further research into antagonistic pleiotropic effects in schizophrenia.

48 echo T2 myelin imaging of white matter in first-episode schizophrenia: evidence for aberrant myelination.

Myelin water imaging provides a novel strategy to assess myelin integrity and corresponding clinical relationships in psychosis, of particular relevance in frontal white matter regions. In the current study, T2 myelin water imaging was used to assess the myelin water fraction (MWF) signal from frontal areas in a sample of 58 individuals experiencing first-episode psychosis (FEP) and 44 healthy volunteers. No differences in frontal MWF were observed between FEP subjects and healthy volunteers; however, differences in normal patterns of associations between frontal MWF and age, education and IQ were seen. Significant positive relationships between frontal MWF and age, North American Adult Reading Test (NAART) IQ, and years of completed education were observed in healthy volunteers. In contrast, only the relationship between frontal MWF and NAART IQ was significant after Bonferroni correction in the FEP group. Additionally, significant positive relationships between age and MWF in the anterior and posterior internal capsules, the genu, and the splenium were observed in healthy volunteers. In FEP subjects, only the relationship between age and MWF in the splenium was statistically significant. Frontal MWF was not associated with local white matter volume. Altered patterns of association between age, years of education, and MWF in FEP suggest that subtle disturbances in myelination may be present early in the course of psychosis.

Treatment delay and pathways to care in early psychosis.

OBJECTIVE: To examine the treatment delay associated with community and inpatient pathways into care for persons experiencing a first episode of psychosis. METHODS: A total of 104 clients entering a specialized early psychosis intervention (EPI) program and their family members were assessed for help-seeking behaviours, psychiatric symptoms, level of functioning and duration of untreated psychosis (DUP). RESULTS: DUP (median = 30.5 weeks) was associated with younger age of onset, poorer engagement with the EPI program and more severe symptoms. Almost one-third of clients had four or more contacts before receiving antipsychotic medication or entering the EPI program and one in five received interventions not specifically indicated for psychosis. Referrals directly involving family members accounted for about 81% of hospital-initiated treatment (39% of all referrals) and 46% of community-initiated treatment (61% of all referrals). Community entry was associated with longer DUP, more time-seeking treatment, younger age of onset, younger age at referral, greater likelihood of receiving other medication or counselling before receiving antipsychotic medication, schizophrenia, less severe symptoms and less substance use in the previous year. Those with schizophrenia showed no differences across pathway type for time-seeking treatment, being provided interventions not specifically indicated for psychosis after onset or rates of substance use. CONCLUSIONS: Treatment delay and the provision of interventions not specifically indicated for psychosis may be increased in first-episode populations who are younger and have less severe symptoms. Improving literacy about early psychosis in both professionals and families merits greater attention.

Effects of eight weeks of atypical antipsychotic treatment on middle frontal thickness in drug-naïve first-episode psychosis patients.

Atypical antipsychotic medications generally maintain or increase gray matter amount and functioning. First-episode psychosis patients have lower gray matter volume in the middle frontal gyrus, as well as worse performance on spatial working memory tasks compared to controls. This study investigated the effects of short-term four- and eight-week atypical treatment on middle frontal thickness and spatial working memory in first-episode psychosis patients. Nineteen drug-naïve first-episode psychosis patients treated with risperidone or quetiapine and 26 controls completed structural magnetic resonance imaging, a spatial working memory task, and clinical assessment at three intervals (baseline, four weeks, and eight weeks; all patients and 23 controls completed all three assessments). Caudal and rostral middle frontal thicknesses were measured using the automated program Freesurfer. Positive, negative, and general symptoms of the Positive and Negative Syndrome Scale (PANSS) decreased significantly in patients, with most of the change occurring in the first four weeks of treatment. Patients demonstrated an increase in rostral middle frontal thickness over eight weeks of treatment compared to controls. There was a medium effect size relationship between reduction in negative symptoms at four and eight weeks, and a change in rostral middle frontal thickness over eight weeks. No changes were found in spatial working memory ability. Short-term atypical treatment with risperidone or quetiapine can increase prefrontal cortical thickness in psychosis. These findings are notable given the role of the rostral middle frontal region in cognition and the relationship between better cognitive functioning and better functional outcome in psychosis.

Antipsychotic medications: linking receptor antagonism to neuropsychological functioning in first episode psychosis.

Antipsychotic medications can contribute to neurocognitive and motor impairments, but specific links to individualized pharmacological treatment regimens are unclear. In 68 participants with stabilized first-episode psychosis (FEP), we investigated the links between neuropsychological functions and an established anticholinergic potency index and a new D(2) antagonist potency index developed in our lab. Each participant's psychiatric medication regimen was converted into estimated receptor antagonist loads based upon specific medication dosage(s) and reported in vitro brain muscarinic cholinergic and D(2) receptor antagonism. In addition to the global neuropsychological impairments of FEP participants, the findings supported the hypothesized links between receptor antagonist loads and specific deficits. Higher anticholinergic load was associated with poorer delayed verbal memory but was not related to motor functioning. In contrast, higher D(2) load was associated with poorer motor functioning but not verbal memory. These selective antagonist load associations explained 19% of the variance in motor functioning and 17% of the variance in delayed verbal memory. Evidently, some of the neuropsychological impairments found in persons with FEP are selectively related to the specific pharmacodynamics and the dosing of their medication regimens. Moreover, these effects can be readily estimated from practical and inexpensive indices.

Hippocampal volume and the brain-derived neurotrophic factor Val66Met polymorphism in first episode psychosis.

INTRODUCTION: Small hippocampi and impaired memory are common in patients with psychosis and brain-derived neurotrophic factor (BDNF) plays a critical role in hippocampal neuroplasticity and memory. A common BDNF allele (Val66Met) has been the focus of numerous studies but results from the few BDNF-imaging studies are complex and contradictory. The objective of this study was to determine the association between Val66Met and hippocampal volume in patients with first episode psychosis. Secondary analyses explored age-related associations and the relationship between Val66Met and memory. METHOD: Hippocampal volume and BDNF genotyping were obtained for 58 patients with first-episode psychosis and 39 healthy volunteers. Patients were recruited from an early psychosis program serving a catchment-area population. RESULTS: Hippocampal volume was significantly smaller in patients than controls (F(1,92)=4.03, p<0.05) and there was a significant group-by-allele interaction (F(1,92)=3.99, p<0.05). Hippocampal volume was significantly smaller in patients than controls who were Val-homozygotes but no group differences were found for Met carriers. Findings were not affected by diagnosis, antipsychotic medication, or age, and there was no change in hippocampal volume during a one-year follow-up. Val-homozygous patients had worse immediate and delayed memory than their Met counterparts. CONCLUSIONS: Results suggest the effects of the BDNF Val66Met allele may be different in patients with psychosis than in healthy adults. Hippocampal volume in patient and control Met allele carriers was very similar suggesting that illness-related factors have minimal influence in this group. In contrast, Val homozygosity was related to smaller hippocampi and poorer memory functioning only in patients with psychosis.

The assessment of symptom severity and functional impairment with DSM-IV axis V.

OBJECTIVE: The Global Assessment of Functioning scale (GAF) is included as axis V in the DSM-IV multiaxial diagnostic system. The GAF is simple to administer and routinely used in treatment planning and as a measure of program performance. The GAF assesses both symptom severity and functional impairment, but the resultant rating provides no information about the contribution of each of these domains. This study aimed to improve the clinical utility of the GAF by creating subscales. METHODS: The authors divided the scale into its two principal domains: descriptors of social and occupational functioning (SOFAS) and descriptors of symptoms (GAF minus SOFAS descriptors). These and other measures of symptoms and functioning were used to assess 407 patients while acutely psychotic and again after treatment. RESULTS: Symptom scores were of greater severity than functional impairment scores in most cases. Because of this, the GAF score tended to reflect symptom severity rather than functional impairment. The symptom rating was more strongly correlated with measures of positive symptoms, and the functional rating had higher associations with negative symptoms and functional impairment. Both scales were good indicators of clinical change. CONCLUSIONS: Findings indicate that GAF ratings for patients with psychosis tend to reflect symptom severity rather than functional impairment. Splitting the GAF into two parts resulted in greater discrimination for this patient group yet retained ease of administration.

An investigation of a possible relationship between olfactory identification deficits at first episode and four-year outcomes in patients with psychosis.

OBJECTIVE: Olfactory identification deficits are found in a significant proportion of patients with schizophrenia spectrum psychotic disorders and appear to be predictive of incomplete remission of negative and cognitive symptoms. In the current study, we examined whether patients with first episode psychosis who have olfactory identification deficits (microsmic) have poorer functional outcome than those whose olfactory status is normal (normosmic). METHOD: Sixty-six (66) first episode psychosis patients (46 M and 20 F) were assessed with the University of Pennsylvania Smell Identification Test (UPSIT) at baseline. UPSIT scores served to classify patients into subgroups. The patients' psychiatrists completed the Social and Occupational Functioning Assessment Scale (SOFAS) and the Levels of Functioning Scale (LOFS) after at least 6 months of treatment. The Premorbid Assessment Scale (PAS) was rated by a parent at baseline. RESULTS: Thirty-eight percent (38%) of the sample was identified as 'microsmic'. LOFS and SOFAS scores were significantly lower in the microsmic group than in the normosmic group. Symptoms were significantly worse in the microsmic group in comparison to the normosmic group. PAS scores did not differ between groups. CONCLUSIONS: First episode patients identified as microsmic at baseline assessment went on to demonstrate poorer functional outcome compared to normosmic patients despite no differences in premorbid adjustment. Olfactory identification deficits at first episode may provide a marker for poorer outcome. Testing olfaction is simple and inexpensive, and could provide clinically valuable information at first episode to identify those patients who might benefit from more intensive interventions promoting functional recovery.

Predictors of starting to smoke cigarettes in patients with first episode psychosis.

INTRODUCTION: Cigarette smoking is common in psychotic disorders and may be initiated in an attempt to control features of illness. However, genetic, obstetric and early life conditions are risks for starting to smoke in the general population but their role in psychotic patients is unclear. METHOD: Smoking history and the putative predictors of starting to smoke were assessed in a community-wide sample of 115 first episode psychosis patients. The proportion that initiated smoking was compared with that from population surveys and the impact of risk factors was assessed within the patient sample. RESULTS: Most patients began smoking before illness onset and the proportion who initiated smoking was significantly high by the onset of a functional decline. Gestational tobacco exposure was a risk for smoking and was also associated with low birthweight, poor academic achievement, and obesity. Low familial socioeconomic position but not familial psychiatric problems also predicted smoking initiation. DISCUSSION: In most cases, smoking preceded illness onset and was not a response to early features of illness. General population predictors of starting to smoke were also associated with smoking initiation in psychotic patients. Of these risks, exposure to tobacco during gestation is noteworthy in that it affects brain development and is associated with cognitive, behavioral, psychiatric and general health problems. In addition, nicotine interacts with other substances of abuse. The initiation of smoking before illness onset and the association with developmental problems raises the question of whether cigarette smoking influences some aspects of illness in patients with psychosis.

Conceptual and methodological issues in the design of clinical trials of antipsychotics for the treatment of schizophrenia.

Schizophrenia is one of the most severe and disabling psychiatric disorders. Antipsychotic drugs offer considerable benefits in controlling symptoms and preventing relapse. The strategy for the present review of clinical trials was to ask 'What are the features of schizophrenia and the existing treatments of the illness that have implications for future clinical trials'? Six key facts were identified.First, schizophrenia is genetically 'complex'. Trials may benefit from designs including genetically related illnesses, by focussing on cross-cutting aspects of the phenotype such as psychosis or cognitive dysfunction, and by collecting information on possible moderators and mediators of treatment response.Second, schizophrenia affects multiple neurotransmitter systems. Multiple signalling pathways may need to be considered, with different time courses of response. Outcome measures from clinical trials could be collected at more frequent intervals, particularly in the early phase of response.Third, the clinical features used to define the illness are a mix of symptoms and social-occupational dysfunction, yet treatment response is often defined only by changes in symptoms. Multiple measures of functioning need to be collected at baseline and at the endpoint of trials. Consensus definitions for response, remission, relapse, recovery and recurrence need to be developed.Fourth, schizophrenia is often highly disabling. Linking treatment response in clinical trials to measures of quality-adjusted life-years will allow comparison with other medical illnesses using common metrics.Fifth, the general health and care of individuals with schizophrenia is often poor. 'Complex' interventions, which include, but are not limited to, antipsychotic medications, need to be designed and tested for the problems facing these patients.Finally, large gaps exist between clinical trials, practice guidelines and patterns of practice. Trials need to be designed to investigate widely used approaches such as antipsychotic polypharmacy, where actual practice diverges from evidence-based guidelines.

Sex differences in olfactory function in young patients with psychotic disorders.

Female superiority on many measures of olfactory function is well established, but debate remains as to whether this pattern extends to patients with psychotic disorders. The purpose of this large retrospective study was to re-examine whether male vs. female differences in olfactory identification exist in patients with psychotic disorders, and if so, whether any such differences were related to features of the psychotic disorder or could be explained by a generalized male-female difference. We examined 353 relatively young patients, recently diagnosed with a psychotic illness, (258 males and 95 females) and compared these with 89 healthy control subjects (45 males and 44 females). All individuals had been assessed birhinally using the University of Pennsylvania Smell Identification Test (UPSIT). Overall, females were superior to males, and patients underperformed healthy controls. No interaction was noted between these two variables, and there was no significant effect found as a result of age of the subjects. The data suggested that sex differences in olfactory identification ability exist in young patients with psychotic disorders. They do not appear to be related to exposure to antipsychotic medication or smoking habit. Therefore, it is likely that they represent basic male vs. female differences and not diagnosis-specific sex differences in olfactory performance-at least in those who are in the early stages of illness.

A longitudinal study on the effects of typical versus atypical antipsychotic drugs on hippocampal volume in schizophrenia.

BACKGROUND: Previous studies have reported that hippocampal volumes correlate with symptom severity in schizophrenia. This longitudinal study measured changes in symptoms and hippocampal volume in patients switched from typical antipsychotics to olanzapine. METHODS: MRI scans were acquired from patients with chronic schizophrenia (n=10) and healthy volunteers (n=20). At baseline, patients were treated with typical antipsychotics for at least one year, then switched to olanzapine, and rescanned approximately one year later. RESULTS: Olanzapine treatment resulted in no significant change in right or left hippocampal volume. Individual changes in right hippocampal volume correlated significantly with changes in symptoms. CONCLUSIONS: Hippocampal volume change may serve as a marker of symptom change in patients on olanzapine.

Reduced thalamic volume in patients with chronic schizophrenia after switching from typical antipsychotic medications to olanzapine.

OBJECTIVE: The authors performed a longitudinal study of the effects on thalamic volume of switching from typical to atypical antipsychotic medications. METHOD: Magnetic resonance imaging scans were acquired from 10 subjects with chronic schizophrenia taking typical antipsychotics and 20 healthy volunteers. Subjects with schizophrenia were switched to olanzapine; both groups were rescanned. RESULTS: At baseline, thalamic volumes in subjects with chronic schizophrenia were 5.8% greater than those of healthy volunteers. At follow-up, there was no significant difference between groups. Additional analysis revealed a significant positive correlation between baseline thalamic volume and dosage of typical antipsychotic medication. Higher dosages at baseline were correlated with larger reductions in volume after the switch to olanzapine. CONCLUSIONS: Antipsychotic medication effects may be a factor in the wide range of thalamic volume differences reported between subjects with schizophrenia and healthy volunteers.

Olfactory identification deficits in first-episode psychosis may predict patients at risk for persistent negative and disorganized or cognitive symptoms.

OBJECTIVE: One-third of patients with a schizophrenia spectrum disorder have a measurable olfactory identification deficit at first examination. The authors studied the relationship of this deficit to symptom remission after 1 year of treatment. METHOD: Fifty-eight patients naive to antipsychotic medication who entered the Nova Scotia Early Psychosis Program were symptomatically rated with the Positive and Negative Syndrome Scale (PANSS) (at baseline and 1 year). At baseline, the University of Pennsylvania Smell Identification Test (UPSIT) was also completed. Remission was determined for four symptom factors derived from the PANSS (positive, negative, cognitive/disorganized, and anxiety/depression). Patients with and without remission were compared on UPSIT scores. RESULTS: Patients with nonremission of negative and cognitive/disorganized symptoms had significantly lower baseline UPSIT scores compared with patients with remission. UPSIT scores were unrelated to remission of positive or anxiety/depression symptoms. CONCLUSIONS: UPSIT scores can be used to identify patients at risk for persistent negative and disorganized/cognitive symptoms.

Treatment of a first episode of psychotic illness with quetiapine: an analysis of 2 year outcomes.

BACKGROUND: The first episode of a psychotic disorder provides a unique opportunity to initiate optimal treatment but when a new medication becomes available, little data exist to guide the appropriate use in this population. OBJECTIVES: The objectives were to determine the optimal doses and titration of quetiapine for this group and to measure outcomes (including symptom response, social functioning, mood alterations, motor symptoms, metabolic parameters and cognitive functioning) over 2 years of treatment with quetiapine. DESIGN: Thirty nine subjects with a first episode of psychosis referred to the Nova Scotia Early Psychosis Program in Halifax, Canada, were invited to participate in this study. Standardized clinical, laboratory, and neuropsychological assessments were performed at baseline and following treatment with quetiapine at intervals out to 2 years. RESULTS: Quetiapine was effective in treating the psychotic and mood symptoms while not causing extra-pyramidal signs or symptoms (EPSS). Pre-existing motor dysfunction improved. No anticholinergic medications were required. Several domains of cognitive function also improved (sustained attention, the number of perseverative errors, visuomotor speed and sequencing, verbal fluency and verbal memory). Weight gain was observed along with increases in cholesterol levels but there was no glucose dysregulation. CONCLUSIONS: The results of this two year, naturalistic study of people with a first episode of psychosis indicated that quetiapine was well tolerated and effective for this population. Significant improvements in cognitive functioning also provided evidence for potential longer-term benefits of early and optimal treatment with this agent. However, monitoring metabolic parameters, as recommended for other atypicals, is likely prudent.

Extrapyramidal symptoms and signs in first-episode, antipsychotic exposed and non-exposed patients with schizophrenia or related psychotic illness.

Movement disorders in first-episode psychosis are increasingly recognized; however, the prevalence and clinical correlates are uncertain. We compared antipsychotic exposed (< 12 weeks) with nonexposed first-episode patients, and report prevalence as well as clinical and demographic variables associated with extrapyramidal dysfunction. Data are baseline assessments from a multicentre, international drug trial of first-episode psychosis (n = 535). Analysis included the Extrapyramidal Symptom Rating Scale, Premorbid Adjustment Scale, and the Positive and Negative Syndrome Scale. Of non-exposed patients, 28.1% (n = 47/167) had at least one mild sign of extrapyramidal dysfunction, as did 46.3% (n = 169/365) of previously exposed patients. Hypokinetic Parkinsonism was the most prevalent disorder. The severity of movement disorders and negative symptoms were correlated; however, the effect sizes were small. Logistic regression analysis indicated that the salient risk factors for all patients were: previous antipsychotic exposure [odds ratio (OR) = 2.4; 95% confidence interval (CI) 1.6-3.6] and poor premorbid functioning (OR = 1.8; 95% CI 1.2-2.6). For the non-exposed group (n = 167), the significant risk factors were: having severe mental illness in the family (OR = 2.9; 95% CI 1.2-7.2) and poor premorbid functioning (OR = 2.3; 95% CI 1.0-5.3). For the previously exposed group (n = 368), the significant variables were: poor premorbid functioning (OR = 1.8; 95%CI 1.2-2.8) and shorter duration of untreated psychosis (OR = 0.78; 95% CI 0.64-0.94). Although antipsychotic exposure was associated with extrapyramidal signs, the results indicate that many first-episode patients with no exposure to antipsychotics also had extrapyramidal dysfunction. In this group, family history and poor premorbid functioning appear to be associated with increased risk for movement disorders.

Hospitalization in the first year of treatment for schizophrenia.

OBJECTIVE: To determine the rates of hospitalization during the first year of treatment for schizophrenia, using an epidemiologic sample. METHOD: We examined inpatient and outpatient administrative databases in the province of Nova Scotia for cases of schizophrenia (ICD-9 code 295 or 298) newly diagnosed during the years 1995 to 1998. We noted the diagnosis site (that is, inpatient or outpatient) and hospitalizations in the year following diagnosis. We also established links to the clinical database maintained by the Nova Scotia Early Psychosis Program (NSEPP). RESULTS: Over the 4-year period, we identified 434 unique cases from an at-risk population of 320,000 (yielding a yearly average age-specific incidence rate of 3.3/10,000), of whom 119 had received care from the NSEPP. Of the cases, 54% were initially diagnosed while they were inpatients. In the year following diagnosis, the overall hospitalization rate, excluding initial hospitalizations, was 17%. Patients who were initially diagnosed while inpatients had a higher rate of hospitalization in the first year of treatment (25% vs 7%), compared with those initially diagnosed while outpatients. This relation was also present among patients who received care from the NSEPP. CONCLUSIONS: Of newly diagnosed patients with schizophrenia, 46% were not hospitalized at the time of initial diagnosis. Of all patients, 17% required hospitalization during the first year of treatment, excluding an initial hospitalization, if present. Hospitalization rates in the first year were higher among patients initially hospitalized and among those with a rural residence. Patients requiring hospitalization during the first year form an important target group for improved interventions.

Reduced basal ganglia volumes after switching to olanzapine in chronically treated patients with schizophrenia.

OBJECTIVE: A follow-up study of patients with schizophrenia was conducted to examine change in striatal volumes and extrapyramidal symptoms after a change in medication. METHOD: Thirty-seven patients with schizophrenia and 23 healthy volunteers were examined. Patients at baseline receiving typical antipsychotics (N=10) or risperidone but exhibiting limited response (N=13) were switched to treatment with olanzapine. Patients receiving risperidone and exhibiting a good response (N=14) continued treatment with risperidone. Caudate, putamen, and pallidal volumes were assessed with magnetic resonance imaging. The Extrapyramidal Symptoms Rating Scale was used to assess clinical signs and symptoms. RESULTS: At baseline, basal ganglia volumes in patients treated with typical antipsychotics were greater than in healthy subjects (putamen: 7.0% larger; globus pallidus: 20.7% larger). After the switch to olanzapine, putamen and globus pallidus volumes decreased (9.8% and 10.7%, respectively) and did not differ from those of healthy subjects at the follow-up evaluation. Akathisia was also reduced. In the patients receiving risperidone at baseline, basal ganglia volumes did not differ between those exhibiting good and poor response, and no significant volume changes were observed in subjects with poor risperidone response after the switch to olanzapine treatment. CONCLUSIONS: Olanzapine reversed putamen and globus pallidus enlargement induced by typical antipsychotics but did not alter volumes in patients previously treated with risperidone. Changes in striatal volumes related to typical and atypical antipsychotics may represent an interactive effect between individual medications and unique patient characteristics.