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.

Cerebral gray matter volume deficits in first episode psychosis.

BACKGROUND: Structural brain differences including decreased gray matter and increased cerebrospinal fluid volumes have been observed in the brains of chronically ill patients with schizophrenia. We hypothesized that deficits in gray matter volume would be present in patients presenting with a first episode of nonaffective psychosis. METHODS: We used magnetic resonance imaging to compare the brains of 77 patients assessed as having a first episode of psychosis (meeting DSM-III-R criteria for schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, or psychotic disorder not otherwise specified) with those of 61 healthy controls matched for age, sex, race, and parental socioeconomic status. Axial, dual-echo scans of the whole brain were segmented into gray matter, white matter, and cerebrospinal fluid compartments using a computerized volumetric approach. These measures were corrected for the significant effects of intracranial volume and age prior to performing between-group comparisons. RESULTS: The first episode psychosis group had significantly smaller gray matter volume (t[136] = -2.2; P = .03) and greater cerebrospinal fluid volume (t[136] = 2.5; P = .02) than normal controls. In the patient group, gray matter volumes were positively correlated with estimates of IQ but not with age of onset, duration of illness, or measures of premorbid functioning. CONCLUSIONS: Deficits in gray matter volume are present in patients experiencing first episode nonaffective psychosis. The magnitude of these differences is smaller than has been described in more chronically ill patients.

Computed tomographic evidence for generalized sulcal and ventricular enlargement in schizophrenia.

Quantification of ventricular and sulcal volumes from the computed tomographic (CT) scans of 45 schizophrenic patients and 57 normal controls was carried out using a semi-automated computerized approach. The sizes of all cerebrospinal fluid spaces measured were significantly related to age in the control population. An age regression model was used to compare patients and controls. Schizophrenics had slightly larger ventricles and considerably larger sulci than controls. Enlargement of the ventricles and sulci was not correlated with measures of negative symptoms or neuropsychological impairment. The CT scans of eight very ill chronically institutionalized schizophrenics were also analyzed. Their CT findings did not differ significantly from the larger group of schizophrenics studied. Our results show that the cerebral atrophy found in schizophrenia is diffuse in nature and does not relate clearly to measures of disease severity or chronicity.

Cerebral gray matter volume deficits after weight recovery from anorexia nervosa.

BACKGROUND: Structural changes have been observed in the brains of low-weight patients with anorexia nervosa (AN), including increased cerebrospinal fluid (CSF) volumes and decreased gray matter and white matter volumes. We hypothesized that subjects who are weight-recovered from AN would show elevated CSF volumes and reduced gray matter volumes compared with controls. METHODS: We used magnetic resonance imaging to compare the brains of 12 subjects who are weight-recovered from AN (time since weight recovery, 1-23 years) with those of 18 healthy control subjects and 13 low-weight patients with AN. Axial, dual-echo scans of the whole brain were segmented into gray matter, white matter, and CSF compartments by means of a computerized volumetric approach. Brain measures were corrected for the significant effects of intracranial volume and age, based on regression analysis of a larger group of 30 healthy female controls. RESULTS: Tests showed that the weight-recovered group had significantly greater CSF volumes and smaller gray matter volumes than the control group. By comparison with low-weight patients, the weight-recovered subjects had significantly smaller CSF volumes and significantly larger gray matter and white matter volumes. In the weight-recovered group, neither the CSF elevations nor gray matter deficits were correlated with the length of time since weight recovery. CONCLUSIONS: The persistent gray matter volume deficits in subjects who are weight-recovered from AN suggest that there may be an irreversible component to the brain changes associated with the illness. The neuropathological features of this irreversible component have yet to be characterized.

Widespread cerebral gray matter volume deficits in schizophrenia.

Magnetic resonance imaging was used to investigate whether the structural brain differences commonly observed in patients with schizophrenia as compared with normal control subjects are specific to gray or white matter, and furthermore whether such abnormalities are localizable to circumscribed cortical regions. Accordingly, 22 patients meeting DSM-III-R criteria for schizophrenia and 20 healthy community volunteers, all 23 to 45 years old, received magnetic resonance imaging scans. Seven axial magnetic resonance imaging sections of 5-mm thickness were segmented into cerebrospinal fluid, gray matter, and white matter compartments and used for volumetric quantification. For the healthy control subjects, age correlated significantly with the percentage of all magnetic resonance imaging sections taken up by gray matter but not white matter. After correcting for the normal effect of age, the schizophrenic group was found to have significantly less gray matter than the control group but no difference in white matter; ventricular volume was 34% greater in the schizophrenic group. The schizophrenic group had less gray matter in all six cortical subregions analyzed; these differences attained statistical significance for all but the parietal measure. These findings have implications for studies of localized gray matter abnormalities and suggest that regional brain volume measurements need to be expressed in the context of possible widespread gray matter volume deficits in schizophrenia.

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.

The contribution of constructional accuracy and organizational strategy to nonverbal recall in schizophrenia and chronic alcoholism.

The Rey-Osterrieth complex figure was used to assess the separate influences of the constructional accuracy and the organizational strategy employed while copying the figure on the later, incidental recall of the figure. We tested a model, which hypothesized that subjects who copied the main framework of the figure holistically would be more likely to achieve good copy accuracy scores and to reproduce the figure more accurately at recall than subjects who used a piecemeal approach during copy. Subjects included 68 detoxified, chronic alcoholics (ALC), 28 patients with schizophrenia (SZ), and 69 normal control subjects (NCS). The results showed that the ALC and the SZ groups, on average, had lower accuracy and strategy scores at copy than did the NCS group, and furthermore, that the combined contributions of copy accuracy and copy strategy accounted for group differences at recall. A path analysis revealed that, for all three groups, copy strategy had a significant direct effect on copy accuracy. Moreover, copy accuracy and copy strategy made independent contributions to recall accuracy within the ALC and NCS groups; by contrast, within the SZ group, copy strategy made an independent contribution to recall performance but copy accuracy did not. These results suggest that (1) organizational strategy can influence constructional accuracy at both copy and recall; (2) copy accuracy and strategy have the potential to influence recall independently; and (3) the recall deficit in ALC could be attributed to abnormalities in both accuracy and strategy at copy, whereas in SZ it could be attributed only to strategy abnormalities. The deficits observed on the complex figure test in the ALC and SZ were primarily nonmnemonic and were related to ability in figure construction and organizational strategy.

Cognitive and motor impairments are related to gray matter volume deficits in schizophrenia.

This study examined whether the neuropsychological deficits observed in patients with schizophrenia were related to cortical gray matter volume deficits in these patients. All subjects were men and included 34 patients with DSM-III-R Schizophrenia and 47 age-matched healthy controls. Subjects received a battery of 21 tests, assessing four different functional domains: executive functions, short-term memory and production, declarative memory, and motor ability. MRI volumes were corrected for normal variation in head size and age, and neuropsychological test scores were corrected for normal variation in age. The schizophrenic group had significantly smaller cortical gray matter volumes (p < .05) and lower test scores in all functional domain than the control group (p = .0001). Within the schizophrenic group, lower scores in each domain were significantly correlated with smaller total cortical gray matter volumes; however, no predictable relationships were observed between neuropsychological test performance and the volumes of specific cortical regions.

A deficit profile of executive, memory, and motor functions in schizophrenia.

This study examined the neuropsychological deficits associated with schizophrenia and the interrelationships among multiple dissociable cognitive and motor functions. The tests were selected for their previously demonstrated sensitivity to circumscribed brain pathology and included four functional domains: executive functions, short-term memory and production, motor ability, and declarative memory. Each test composite was divided according to verbal versus nonverbal material or left- versus right-hand performance; this distinction permitted functions principally subserved by the left or right cerebral hemispheres to be tested separately. Data reduction was theoretically driven by the test selection and was achieved first by standardizing the scores of each test for age-related differences observed in the normal control group, and then by calculating test composite scores as an average of the age-corrected Z-scores of the tests comprising a functional composite. The schizophrenic group was impaired equivalently on all composites for both cerebral hemispheres; on average, the Z-scores of the patients were 1 standard deviation below those of the control group. The cognitive test composite scores were highly intercorrelated but showed only weak associations with motor ability. Multiple regression analyses suggested that symptom severity was a significant predictor of the Declarative Memory and Short-Term Memory/Production composite scores after accounting for disease duration, whereas disease duration uniquely contributed to the Executive Functions composite scores after controlling for symptom severity. Even though the schizophrenics as a group showed an equivalent level of deficit across all test composites, 1) the deficits were associated with different aspects of psychiatric symptomatology, 2) the motor deficit was independent of the cognitive deficits, and 3) each neuropsychological domain contributed independently to the deficit pattern. Thus, what appears to be a generalized functional deficit in schizophrenia may actually be, at least in part, combinations of multiple specific deficits.

Volumetric MRI assessment of temporal lobe structures in schizophrenia.

This magnetic resonance imaging (MRI) study was designed to investigate whether patients with schizophrenia have focal or lateralized deficits in the volumes of temporal lobe structures. Estimated volumes of the temporal lobes, hippocampi, superior temporal gyri, lateral ventricles, third ventricle, temporal horns of the lateral ventricles, and a frontal-parietal reference area (FPRA) were quantified for each hemisphere. The schizophrenic group had less gray matter (GM) in the temporal lobes and the FPRA relative to controls. Ventricular volumes were significantly larger in the schizophrenic group, as was cerebrospinal fluid (CSF) volume for temporal lobe sulci. No significant differences in hippocampal volumes emerged between groups. The magnitude of GM deficit was not greater in the temporal lobes relative to the FPRA. These results confirm the presence of bilateral GM volume deficits of the temporal lobes in schizophrenia but do not support the hypothesis that structural changes preferentially affect the temporal lobes or the left cerebral hemisphere.

Temporal horn enlargement is present in schizophrenia and bipolar disorder.

BACKGROUND: Ventricular enlargement and temporal lobe volume deficits have been demonstrated in patients with affective disorder as well as those with schizophrenia. This study compares quantitative measures of temporal lobe, hemispheric, and ventricular volumes in a group of patients with chronic schizophrenia and bipolar disorder and seeks to determine if the groups can be differentiated on the basis of measured brain abnormalities. METHODS: A series of coronal magnetic resonance imaging sections were acquired and analyzed for each of 22 patients with chronic schizophrenia, 14 patients with bipolar disorder, and 15 community volunteers. Eleven regions of interest for each brain were defined, which included temporal lobe, superior temporal gyrus, hemisphere, lateral ventricle, third ventricle, and temporal horn measures. Tissue measures were obtained by tracing, and cerebrospinal fluid measures were obtained by fluid-tissue thresholding using specialized computer software. RESULTS: Both patient groups had significantly larger temporal horn volumes in comparison with the control group both before and after correction for intracranial volume. The two patient groups did not differ from each other or controls on any other tissue or fluid measure. CONCLUSIONS: This study confirms the findings of increased temporal horn volume in patients with schizophrenia and suggests that this structural abnormality does not differentiate the structural neuropathology of schizophrenia from that of bipolar disorder.

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.

Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia.

OBJECTIVE: Dopamine D2 receptor occupancy measurements provide a valid predictor of antipsychotic response, extrapyramidal side effects, and elevation of prolactin levels. The new antipsychotics clozapine, risperidone, and olanzapine obtain antipsychotic response with few extrapyramidal side effects and little prolactin elevation. The purpose of this study was to compare the D2 and serotonin 5-HT2 receptor occupancies of these drugs in patients receiving multiple-dose, steady-state regimens. METHOD: Forty-four patients with schizophrenia (16 taking risperidone, 2-12 mg/day; 17 taking olanzapine, 5-60 mg/day; and 11 taking clozapine, 75-900 mg/day) had their D2 and 5-HT2 occupancies determined with the use of [11C]raclopride and [18F]setoperone, respectively, and positron emission tomography imaging. RESULTS: Clozapine showed a much lower D2 occupancy (16%-68%) than risperidone (63%-89%) and olanzapine (43%-89%). Risperidone and olanzapine gave equal D2 occupancies at doses of 5 and 20 mg/day, respectively. All three drugs showed greater 5-HT2 than D2 occupancy at all doses, although the difference was greatest for clozapine. CONCLUSIONS: Clozapine, at doses known to be effective in routine clinical settings, showed a D2 occupancy clearly lower than that of typical antipsychotics, while risperidone and olanzapine at their usual clinical doses gave the same level of D2 occupancy as low-dose typical antipsychotics. The results also suggest that some previous clinical comparisons of antipsychotics may have been confounded by different levels of D2 occupancy. Clinical comparisons of these drugs, matching for D2 occupancy, may provide a better measure of their true "atypicality" and will help in understanding the contribution of non-D2 receptors to antipsychotic effects.

5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation.

OBJECTIVE: Olanzapine is a new atypical antipsychotic recently introduced for the treatment of schizophrenia. The purpose of this study was to investigate olanzapine's binding to the serotonin 5-HT2 and dopamine D2 receptors in schizophrenic patients being treated with clinically relevant doses. METHOD: Twelve patients with schizophrenia were randomly assigned to 5, 10, 15, or 20 mg/day of olanzapine in a prospective fashion. Three other subjects taking 30-40 mg/day were also included. Once steady-state plasma levels were achieved, dopamine D2 and serotonin 5-HT2 receptors were assessed by using [11C]raclopride and [18F]setoperone positron emission tomography imaging, respectively. Ratings of clinical status, extrapyramidal side effects, and prolactin levels were also obtained. RESULTS: Olanzapine induced near saturation of the 5-HT2 receptors, even at 5 mg/day. Its D2 occupancy increased with dose: patients taking 5-20 mg/day showed 43%-80% D2 occupancy, while patients taking 30-40 mg/day showed 83%-88%. CONCLUSIONS: Olanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses. However, its D2 occupancy is higher than that of clozapine and similar to that of risperidone. In the usual clinical dose range of 10-20 mg/day, its occupancy varies from 71% to 80%, and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation. However, doses of 30 mg/day and higher are associated with more than 80% D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects.

Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects.

OBJECTIVE: Several postmortem studies have reported a decreased density of serotonin 5-HT2 receptors in the prefrontal cortex in schizophrenia. The purpose of this study was to investigate this in patients with schizophrenia by means of [18F]setoperone and positron emission tomography (PET) imaging. METHOD: Thirteen neuroleptic-free patients with schizophrenia, 10 of whom were also neuroleptic-naive, were compared with a group of 26 normal subjects in the same age range. The density of 5-HT2 receptors was assessed with the use of [18F]setoperone and PET in standardized cortical regions of interest. RESULTS: Increasing age was associated with similar declines in 5-HT2 receptors in all cortical regions in the patient group and in the normal comparison group. After control for the effect of age, there was no statistically significant difference between the patients and the comparison subjects in 5-HT2 receptor density in any of the cortical regions. CONCLUSIONS: This study failed to find the decrease in 5-HT2 receptors reported in postmortem studies of schizophrenia. The study had the power to detect a decrease of 25% or more in 5-HT2 receptors, which was anticipated on the basis of the previous postmortem studies. Thus, a primary serotonergic abnormality in schizophrenia, if one exists, is either small or unlikely to be at the level of the 5-HT2 receptors. This finding does not rule out a therapeutic role for 5-HT2 antagonists in schizophrenia, but it does suggest that the therapeutic contribution is likely to be an indirect one.

A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood.

OBJECTIVE: To model in vivo the dynamic interrelations of head size, gray matter, white matter, and cerebrospinal fluid (CSF) volumes from infancy to old age using magnetic resonance imaging (MRI). DESIGN: Cross-sectional, between-subjects using an age-regression model. SETTING: A Veterans Affairs medical center and community hospitals. PARTICIPANTS: There were 88 male and female subjects aged 3 months to 30 years whose clinical MRI film had been read as normal and 73 healthy male volunteers aged 21 to 70 years who had an MRI performed specifically for this study. MAIN OUTCOME MEASURES: These MRI data were quantified using a semiautomated computer technique for segmenting images into gray matter, white matter, and CSF compartments. The cortex was defined geometrically as the outer 45% on each analyzed slice, and the volumes of cortical white matter, gray matter, and CSF were computed. Subcortical (ventricular) CSF volume was computed for the inner 55% of each analyzed slice. RESULTS: In the younger sample, intracranial volume increased by about 300 mL from 3 months to 10 years. The same patterns of change in volume of each compartment across the age range were seen in both sexes: cortical gray matter volume peaked around age 4 years and decreased thereafter; cortical white matter volume increased steadily until about age 20 years; cortical and ventricular CSF volumes remained constant. In the older sample, brain volumes were statistically adjusted for normal variation in head size through a regression procedure and revealed the following pattern: cortical gray matter volume decreased curvilin-early, showing an average volume loss of 0.7 mL/y, while cortical white matter volume remained constant during the five decades; complementary to the cortical gray matter decrease, cortical CSF volume increased by 0.6 mL/y and ventricular volumes increased by 0.3 mL/y. CONCLUSIONS: These patterns of growth and change seen in vivo with MRI are largely consistent with neuropathological studies, as well as animal models of development, and may reflect neuronal progressive and regressive processes, including cell growth, myelination, cell death, and atrophy.

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.

The D2 receptor occupancy profile of loxapine determined using PET.

Positron emission tomography (PET) studies of typical neuroleptics suggest that 60% to 80% of striatal D2 occupancy may be sufficient for optimal clinical treatment of psychosis. Therefore, striatal D2 occupancy may be used as an index to determine the optimal dose range. Toward this end, we determined the in vivo D2 profile of loxapine, using [11C]-raclopride and PET. Seven patients selected from a clinical population were scanned while taking steady-state oral loxapine from 10 to 100 mg/day. Their D2 receptor occupancy was estimated by comparing them to age-matched data from neuroleptic-naive patients. The D2 receptor occupancy ranged from 52% to 90%, and there was a very strong relationship between dose and D2 occupancy, suggesting that 15 to 30 mg/day of loxapine would produce, the putatively optimal, 60% to 80% striatal D2 blockade. This dose range is much lower than that used in most clinical settings and points to the potential efficacy of loxapine at lower doses.

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.