Ethnic diversity and pathways to care for a first episode of psychosis in Ontario.

OBJECTIVE: To examine ethnic variations in the pathways to care for persons accessing early intervention (EI) services in Ontario. METHOD: The pathways to care and the duration of untreated psychosis were assessed for first-episode psychosis patients who entered specialized EI services in Ontario. The sample was assigned to the following ethnic classifications: the White (Caucasian), Black (African descent), and Asian (ancestry from the continent) groups, plus all the "other ethnicities" group. RESULTS: There were 200 participants: 78% were male; 61% from the White, 15% Black, 13% Asian, and 11% were from the other ethnicities group. At the first point of contact, more participants used nonmedical contacts (12%), such as clergy and naturopathic healers, than psychologists (8%) or psychiatrists (7%). There were no ethnic differences for duration of untreated psychosis (median 22 weeks) or for initiation of help seeking by family/friends (53%), police (15%), or self (33%). After adjusting for relevant clinical and demographic factors, the Asian and other ethnicities groups were 4 and 3 times (respectively) more likely than the White or Black groups (P = .017) to use emergency room services as the first point of contact in the pathways to care. Participants from the Asian group experienced less involuntary hospitalizations (P = .023) than all the other groups. Yet overall, there were many more similarities than significant differences in the pathways to care. CONCLUSION: EI services should monitor the pathways to care for young people of diverse ethnic backgrounds to address any disparities in accessing care.

A multi-site Canadian perspective: examining the functional outcome from first-episode psychosis.

OBJECTIVE: To examine factors contributing to variance in functional outcome in first-episode psychosis (FEP) following 1 year of treatment. METHOD: Naturalistic 1-year follow-up of a FEP cohort (n = 200), from programs in four university centers in Ontario, Canada. Functional recovery was defined by 'Social and Occupational Functioning Assessment Scale' (SOFAS) score>60. Regression analysis examined the contribution of independent variables to variance in functional outcome. RESULTS: Twelve-month outcome measures were available for 76.5% of the original cohort. Of these, 70% reported being in school/work and in satisfactory relationships. The functional recovery rate was 51%, compared to 74% attaining symptomatic remission. The greatest contributors to variance in outcome were ongoing symptoms at 6 months and substance abuse comorbidity. CONCLUSION: After 1 year of treatment, FEP patients show high rates of symptomatic remission and relatively lower rates of functional recovery. Symptoms and substance abuse contribute to variance in outcome.

Olanzapine and haloperidol in first episode psychosis: two-year data.

Few studies have assessed the comparative efficacy and safety of atypical and typical antipsychotic medications in patients within their first episode of psychosis. This study examined the effectiveness of the atypical antipsychotic olanzapine and the typical antipsychotic haloperidol in patients experiencing their first episode of a schizophrenia-related psychotic disorder over a 2-year treatment period. Two hundred and sixty-three patients were randomized to olanzapine or haloperidol in a doubleblind, multisite, international 2-year study. Clinical symptoms and side effects were assessed at baseline and longitudinally following randomization for the duration of the study. Olanzapine and haloperidol treatment were both associated with substantial and comparable reductions in symptom severity (the primary outcome measure) over the course of the study. However, the treatment groups differed on two secondary efficacy measures. Patients were less likely to discontinue treatment with olanzapine than with haloperidol: mean time (in days) in the study was significantly greater for those treated with olanzapine compared to haloperidol (322.09 vs. 230.38, p<0.0085). Moreover, remission rates were greater in patients treated with olanzapine as compared to those treated with haloperidol (57.25% vs. 43.94%, p<0.036). While extrapyramidal side effects were greater in those treated with haloperidol, weight gain, cholesterol level and liver function values were greater in patients treated with olanzapine. The data from this study suggest some clinical benefits for olanzapine as compared to haloperidol in first episode patients, which must be weighed against those adverse effects that are more likely with olanzapine.

A systematic review of longitudinal outcome studies of first-episode psychosis.

BACKGROUND: Existing outcome literature has had an over-representation of chronic patients and suggested a progressive course and poor outcome for schizophrenia. The current study aimed to recombine data of samples from longitudinal studies of first-episode psychosis (FEP) to describe outcome and its predictors. METHOD: A literature search (1966-2003) was conducted for prospective studies examining outcome in first-episode non-affective psychosis using the following key words: early, first, incident, episode, admission, contact, psychosis, schizophrenia, psychotic disorders, course, outcome, follow-up, longitudinal, cohort. These were pooled and analyzed using descriptive and regression analyses. RESULTS: Thirty-seven studies met the inclusion criteria, representing 4100 patients with a mean follow-up of 35.1+/-6.0 months. Studies varied in the categories of outcome used, the most common being 'good' (54% of studies) and 'poor' (34% of studies), variably defined. In studies reporting these categories, good outcomes were reported in 42.2% (3.5%) and poor outcomes in 27.1% (2.8%) of cases. Predictors associated with better outcome domains were: combination of pharmacotherapy and psychosocial therapy, lack of epidemiologic representativeness of the sample, and a developing country of origin. Use of typical neuroleptics was associated with worse outcome. Stratification analyses suggested that populations with schizophrenia only, and those with prospective design, were associated with worse outcome domains. CONCLUSIONS: Outcome from FEP may be more favorable than previously reported, and treatment and methodological variables may be important contributors to outcome. Significant heterogeneity in definitions and methodology limited the comparison and pooling of data. A multi-dimensional, globally used definition of outcome is required for future research.

Factorial structure of the Scale of Prodromal Symptoms.

Data from the Scale of Prodromal Symptoms (SOPS) [Early Intervention in Psychotic Disorders, pp. 135-150] on 94 hitherto never-psychotic individuals were entered into a principal components analysis, revealing six components with an eigenvalue greater than 1.0. Based upon scree-plot analysis, further extractions were limited to three, then two, factors. Varimax rotation of the three-component extraction revealed factors with reasonable congruence with a priori content areas. All symptoms labeled as negative in the SOPS loaded on one factor, and four of five symptoms labeled as positive loaded on another. The remaining positive symptom, conceptual disorganization, has been found not to load with other positive-labeled symptoms in studies of schizophrenia using applicable instruments. All symptoms labeled as "general" in the SOPS loaded on a third factor, which appears to reflect the nonspecific psychological distress that might be expected in psychosis-naïve individuals experiencing the preliminary stages of a serious psychiatric disorder. The independence of this component from the positive and negative symptom factors suggests that the structure obtained suggests a clinical continuity between the at-risk presentations seen in this sample and established schizophrenia.

The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. II. Baseline characteristics of the "prodromal" sample.

The first double-blind placebo-controlled clinical trial of an atypical neuroleptic medication is being conducted in symptomatic treatment-seeking patients meeting new diagnostic criteria for a putative prodromal syndrome. This identifies them as being at high risk for developing psychosis in the near future. The study aims include prevention of psychosis onset and disability, as well as palliation of ongoing symptomatology. The purpose of this report is to describe the study's "prodromally symptomatic" sample at baseline, i.e., at intake immediately prior to randomization and prior to receiving study medication. Sixty treatment-seeking patients meeting prodromal inclusion criteria were recruited across four sites: New Haven, CT (n=39), Toronto, Ontario (n=9), Calgary, Alberta (n=6), and Chapel Hill, NC (n=6). The sample was young (median age 16), largely male (65%), and came from families with high titers of serious mental illness (44%). Most patients (93%) met criteria for the Attenuated Positive Symptom (APS) prodromal syndrome and presented with significant but nonpsychotic suspiciousness, perceptual aberrations, unusual thought content, and conceptual disorganization. They presented with minimal to mild affective symptoms and substance use/abuse, but they were quite functionally compromised (mean Global Assessment of Functioning (GAF) score=42). The prodromal sample was compared with other clinical-trial samples of adolescent depression, adolescent mania, and first episode schizophrenia. Prodromal patients proved not to be depressed or manic. They were less severely ill than untreated first episode schizophrenia but more severely ill than treated first episode schizophrenia. While not psychotically disabled, these patients nevertheless present with a clinical syndrome. Subsequent reports will detail the effects of drug versus placebo on prodromal symptoms, neuropsychological profile, and the rate of conversion to psychosis.

The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. I. Study rationale and design.

The first double-blind placebo-controlled clinical trial of an atypical neuroleptic medication is being conducted in symptomatic treatment-seeking patients meeting new diagnostic criteria for a putative prodromal syndrome. This identifies them as being at high risk for developing psychosis in the near future. The study aims include prevention of psychosis onset and disability, as well as palliation of ongoing symptomatology. This report presents the study rationale and design. Recent studies will be reviewed that have advanced our knowledge about the early course of schizophrenia and our ability to predict onset prospectively, advances that have rendered prodromal intervention research feasible and ethical. The study design has many novel features. It tests for prevention versus delay in psychosis onset, as well as for efficacy and safety in a newly defined clinical population. This has required the development of innovative clinical research assessment instruments and a new operational definition of psychosis onset. The integration of these novel elements into an otherwise typical clinical trial design is detailed. The companion report will address sample recruitment and the clinical phenomenology at baseline of this putative "prodromal" entity.

Significant dissociation of brain and plasma kinetics with antipsychotics.

Current dosing regimens of psychotropic drugs are based on plasma kinetic considerations, although it is unclear whether plasma levels faithfully reflect brain kinetics of drugs.(1,2) To examine this, we compared the kinetics of plasma levels of two widely used antipsychotics, olanzapine and risperidone, vs the time course of their effects in the brain. We used positron emission tomography (PET) and [(11)C]-labeled ligands to quantify striatal and extra-striatal dopamine-2 (D(2)), and cortical serotonin-2A (5-HT(2A)) receptor occupancy in healthy subjects after a single dose, and in patients chronically treated for psychosis. We found a significant dissociation of brain and plasma kinetics. Mean plasma elimination half-lives of single doses of olanzapine and risperidone were 24.2 and 10.3 h, respectively, whereas it took on average 75.2 h with olanzapine, and 66.6 h with risperidone to decline to 50% of their peak striatal D(2) receptor occupancy. We found similar discrepancies between the time course of plasma levels and extra-striatal D(2) as well as 5-HT(2A) receptor occupancy. Our results question the current reliance on plasma kinetics as the main basis for dosing regimens of antipsychotics. Studies of brain kinetics may provide a sounder basis for determining dosing schedules of psychotropic medications.

Motor sequencing deficits in schizophrenia: a comparison with Parkinson's disease.

Motor abnormalities occur in schizophrenia (SZ) and may arise from striatal dysfunction. This study examined whether the pattern of performance on simple and complex motor abilities in SZ was similar to that of patients with Parkinson's disease (PD). Quantitative tests of speeded movement and motor and cognitive sequencing were used to assess 25 SZ, 16 PD, and 84 normal controls (NCs). Sequencing performance was also examined with motor rigidity taken into account. Compared with the NC group, the SZ and PD groups were impaired on measures of motor rigidity and motor sequencing. With rigidity accounted for, the SZ group was significantly more impaired than the PD group on motor sequencing; cognitive and motor processes contributed to the motor deficit. Cognitive sequencing performance predicted motor sequencing performance in PD but not SZ. Although both SZ and PD resulted in significant motor and cognitive sequencing deficits, the pattern and correlates of these deficits differ, suggesting that the affected neural systems underlying motor deficits in SZ are different from those involved in PD.

A simple method to measure baseline occupancy of neostriatal dopamine D2 receptors by dopamine in vivo in healthy subjects.

The effect of endogenous dopamine (DA) on measurement of neostriatal DA D(2) receptor binding potential (D(2)RBP) in vivo was evaluated with positron emission tomography (PET) and the radiotracer [11C]raclopride by comparing the D(2)RBP before and after acute DA depletion. DA depletion was achieved by per-oral administration of 4.5 g alpha-methyl-para-tyrosine (AMPT) given in 25 h. Six healthy subjects completed the protocol. The AMPT treatment increased D(2)RBP significantly from 3.11 +/- 0.25 to 3.68 +/- 0.23 and decreased plasma levels of the DA metabolite homovanillic acid by 71 +/- 11% and levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenethyleneglycol by 53 +/- 7%. Increase in D(2)RBP correlated with decrease in attentiveness and with increase in errors of commission from Conners' Continuous Performance Test. On AMPT, a significant decrease in subjective happiness scores was observed. The results imply that a noninvasive [11C]raclopride PET protocol coupled with relatively brief administration of a rather low total dose of AMPT resulted in measurable acute DA depletion that might provide estimates of synaptic neostriatal DA concentration.

Auditory feature conjunction in patients with schizophrenia.

The neural mechanisms supporting performance during single feature and feature conjunction tasks were investigated in patients with schizophrenia and age-matched controls using event-related brain potentials. In different blocks of trials, participants responded to auditory targets defined by one of two pitches, one of two locations, or both pitch and location. All participants were faster and more accurate in detecting targets defined by a single feature than for targets defined by a conjunction of features. Compared with the single feature conditions, conjunction targets were associated with enhanced negativity between 200 and 250ms (N2) post-stimulus and showed a delayed P3b latency. Compared with controls, patients with schizophrenia showed reduced N1 and N2 amplitude elicited by single and conjunctive targets. The results are consistent with defective perceptual mechanisms in schizophrenia. The fact that both performance and P3b amplitude were similar in patients and controls suggests that controlled processes compensate for processes normally carried out by early perceptual mechanisms.

Starving the brain: structural abnormalities and cognitive impairment in adolescents with anorexia nervosa.

Anorexia nervosa (AN) is one of the most common chronic illnesses afflicting adolescent girls and is associated severe medical complications. The structural abnormalities found in the brain of adolescents with AN are among the earliest and most striking physical consequences. In the past, it had been assumed that the brain abnormalities found in patients with AN reverse with weight-recovery. Recent evidence has shown that not all of these changes are completely reversible with weight recovery. To date, very little is known about the functional significance of these brain abnormalities. Several studies have shown that cognitive dysfunction is also a common feature of AN. Although current evidence suggests that there may be some degree of improvement in cognition with weight-recovery, it is unclear whether cognition recovers fully or equally across all neuropsychological domains. Furthermore, it remains unknown whether the reported functional consequences are associated with these structural brain changes. This article will review the current literature on structural brain abnormalities and cognitive dysfunction in adolescents with AN.

Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study.

RATIONALE: Dopamine D2 receptor upregulation in the striatum is regularly seen in response to the administration of traditional antipsychotics in animal experiments. This is associated with hyperactivity and, for this reason, D2 receptor upregulation has long been postulated as central to tardive dyskinesia (TD). OBJECTIVE: Using positron emission tomography (PET), the present study attempted to determine whether antipsychotic-induced D2 receptor up-regulation also occurs in humans. METHODS: The long-term effects of traditional and novel antipsychotics on dopamine D2 receptors were investigated in nine subjects meeting DSM-IV criteria for schizophrenia who were deemed eligible for temporary treatment washout. Subjects had been treated with traditional antipsychotics (haloperidol n=3, perphenazine n=1) and novel antipsychotics (risperidone n=3, olanzapine n=2) in the moderate to high dosage range. Fourteen days after treatment withdrawal, the binding potentials (BPs) of dopamine D2 receptors were measured using 11[C] raclopride. The obtained BPs were compared to the BPs from antipsychotic-naive control subjects with schizophrenia. RESULTS: There was a significant increase in the D2 BP in both groups combined that reached 34%. The increases in the D2 BPs in the groups treated with conventional and novel antipsychotics were 37% and 31%, respectively. Significantly, the patients showing the highest degree of D2 receptor upregulation (98%) developed severe and persistent TD shortly after being started on a new antipsychotic with low affinity for D2 receptors. CONCLUSION: This study demonstrates for the first time, using in vivo neuroreceptor imaging, that dopamine D2 receptor binding is increased after long-term treatment with antipsychotics in humans. The data suggest that both traditional and novel antipsychotics with high affinity for dopamine D2 receptors are associated with a substantial increase in D2 receptor binding. The present data in humans agree well with animal data that implicate D2 receptor-mediated mechanisms in motor hyperactivity.

A voxel-by-voxel analysis of [18F]setoperone PET data shows no substantial serotonin 5-HT(2A) receptor changes in schizophrenia.

Several postmortem studies have reported regionally localized decreases in serotonin(2A) receptors (5-HT(2A)R) in schizophrenia. This was not confirmed by two recent [18F]setoperone positron emission tomography (PET) studies. In these two studies relatively large regions of interest (ROIs) were used; hence, 5-HT(2A)R changes may have been missed in some brain areas. Therefore, data from one study were analyzed on a voxel-by-voxel basis using Statistical Parametric Mapping (SPM). We also used this method to examine the relationship between 5-HT(2A)R binding potential (BP) and five PANSS-derived factors: negative, positive, activation, dysphoric and autistic preoccupation. Thirteen schizophrenic patients (10 antipsychotic-naïve, 3 antipsychotic-free; 11 M, 2 F; age 31+/-7 years) and 35 age-matched control subjects (15 M, 20 F; age 30+/-7 years) were scanned. The 5-HT(2A)R BP was determined for each voxel using the pseudoequilibrium ratio method on PET data obtained between 65 and 90 min after [18F]setoperone bolus injection. The resulting parametric 5-HT(2A)R BP images were spatially normalized using a ligand specific template. Analyses of covariance were done using SPM99 with age as covariate. In tests for the effect of schizophrenia and for partial correlations between 5-HT(2A)R BP and the five factors, corrected P values <0.05 at cluster or voxel level were considered significant. No significant differences were detected between patients and control subjects, and no significant correlations were observed between 5-HT(2A)R BP and any of the five factors. Thus, in agreement with the previous ROI studies, voxel-by-voxel analysis confirmed the lack of substantial 5-HT(2A)R BP differences between schizophrenic patients and control subjects.

Predicting haloperidol occupancy of central dopamine D2 receptors from plasma levels.

Positron emission tomography (PET) is increasingly being used to study dopamine receptor occupancy and the clinical effects of antipsychotic medication. Dopamine D2 receptor occupancy has been shown to predict several clinical effects of antipsychotic medication including therapeutic response, motor and endocrine side-effects. Plasma levels may be used as a surrogate marker for central occupancy if the relationship between these two measures may be accurately described. This study was designed to test the capacity of a previously derived relationship equation (%D2 occupancy=plasma level/ED50+plasma level, where ED50= 0.40 ng/ml) to predict striatal D2 occupancy from plasma level. Twenty-one patients receiving treatment with low dose haloperidol underwent a 11C-raclopride PET scan to measure D2 occupancy. The D2 occupancy levels were accurately predicted by use of the previously generated equation with only a small degree of error (3.89% CI 0.45-7.33). Predicted and measured D2 occupancy values correlated closely (Pearson's r=0.864, P=0.003). The study indicates that reliable prediction of D2 occupancy from plasma levels is possible. This provides a potentially useful surrogate measure of D2 occupancy for research and possibly clinical practice, as the routine use of PET to measure occupancy levels is not feasible.

Instrumentally detected changes in motor functioning in patients with low levels of antipsychotic dopamine D2 blockade.

Extrapyramidal side-effects (EPSE) of antipsychotic medication are related to the occupancy of dopamine D2 receptors and there appears to be a threshold of D2 occupancy below which clinically EPSE are unlikely to occur. It is unclear whether there are motor changes produced by 'subthreshold' levels of D2 occupancy that are not detectable by clinical examination. This study was designed to investigate whether a number of electromechanical instrumental techniques could detect 'subthreshold' motor changes and whether these changes correlate with dopamine D2 occupancy as measured by [11C]-raclopride PET scan. Twenty medication naïve patients were studied before and during treatment with low dose haloperidol. Instrumental techniques detected an asymmetrical worsening in motor function with drug treatment despite the failure of the group to experience significant EPSE. These changes did not correlate with D2 occupancy and measurements of rigidity, tremor, and bradykinesia did not closely inter-correlate.

Qualitative MRI findings in adults with 22q11 deletion syndrome and schizophrenia.

BACKGROUND: A genetic syndrome associated with schizophrenia, 22q11 deletion syndrome (22qDS), may represent a genetic subtype of schizophrenia (22qDS-Sz). Structural brain changes are common in schizophrenia and may involve developmental anomalies, but there are no data yet for 22qDS-Sz. The objective of this study was to assess brain structure in adults with 22qDS-Sz using magnetic resonance imaging (MRI). METHODS: Brain and arterial MRI scans of 11 adults with 22qDS-Sz (mean age = 28.4 years, SD = 6.5) were systematically assessed by a neuroradiologist for qualitative anomalies. RESULTS: A high frequency of abnormalities were found: T2 white matter bright foci (BF), 90%; developmental midline anomalies, 45%; cerebral atrophy or ventricular enlargement, 54%; mild cerebellar atrophy, 36%; skull base abnormalities, 55%; and minor vascular abnormalities, 36%. CONCLUSIONS: BF and skull base abnormalities, especially in association with neurodevelopmental midline abnormalities, may be distinguishing MRI features for a genetic subtype of schizophrenia involving a deletion on chromosome 22.

Is amoxapine an atypical antipsychotic? Positron-emission tomography investigation of its dopamine2 and serotonin2 occupancy.

BACKGROUND: All currently available atypical antipsychotics have, at clinically relevant doses: i) high serotonin (5-HT)2 occupancy; ii) greater 5-HT2 than dopamine (D)2 occupancy; and iii) a higher incidence of extrapyramidal side effects when their D2 occupancy exceeds 80%. A review of pharmacologic and behavioral data suggested that amoxapine should also conform to this profile; therefore, we undertook a positron-emission tomography (PET) study of its 5-HT2 and D2 occupancy. METHODS: Seven healthy volunteers received 50-250 mg/day of amoxapine for 5 days and then had [11C]-raclopride and [18F]-setoperone PET scans. RESULTS: 5-HT2 receptors showed near saturation at doses of 100 mg/day and above. The D2 receptor occupancies showed a dose-dependent increase, never exceeding 80%; at all doses 5-HT2 occupancy exceeded D2 occupancy. CONCLUSIONS: PET data show that amoxapine's profile is very similar to that of the established atypical antipsychotics. These data, together with amoxapine's in vitro pharmacologic profile, effectiveness in animal models, and efficacy in psychotic depression raise the possibility of amoxapine as an "atypical" antipsychotic agent in the treatment of schizophrenia.

Placebo-controlled studies in schizophrenia--ethical and scientific perspectives: an overview of conference proceedings.

Much controversy has surrounded the issue of whether clinical trials of new antipsychotic medications for the treatment of schizophrenia ought to include a placebo control group. On 18 September 1997, the authors co-chaired a symposium at the University of Toronto devoted to elucidating the issues relevant to this debate. Speakers with expertise in the areas of schizophrenia research, clinical trials methodology, medical ethics and informed consent presented their perspectives. This paper aims to summarize the major scientific and ethical issues raised during the symposium.

Optimal haloperidol dosage in first-episode psychosis.

OBJECTIVE: To determine optimal doses of haloperidol for the treatment of a first episode of psychosis. METHOD: A 4-week prospective controlled clinical trial with "optimal dose" defined as the dose at which either of the following occurs: 1) significant improvement, defined as a 15% or greater decrease in scores on the Positive And Negative Syndrome Scale (PANSS), or 2) the onset of extrapyramidal symptoms. Beginning with 2 mg daily, haloperidol was increased weekly to 5 mg, 10 mg, and finally 20 mg daily until either 1) or 2) occurred. RESULTS: Optimal doses for the 36 subjects were 2 mg daily for 15 subjects, 5 mg daily for 11, 10 mg daily for 7, and 20 mg daily for 3. On average, subjects whose optimal dose was 2 mg daily showed the greatest improvement. Among the 27 subjects evidencing clinical response to treatment, 20 had plasma haloperidol levels below 5 ng/ml. CONCLUSION: Many people suffering a first psychotic episode respond to haloperidol doses well below levels in common use.