Trajectories of depressive symptoms in the acute phase of psychosis: Implications for treatment.

Depression is common in schizophrenia and associated with negative outcomes. Previous studies have identified heterogeneity in treatment response in schizophrenia. We aimed to investigate different trajectories of depression in patients suffering from psychosis and predictors of change in depressive symptoms during antipsychotic treatment. Two hundred and twenty-six patients >18 years acutely admitted due to psychosis were consecutively included and the follow-up was 27 weeks. The Calgary Depression Scale for Schizophrenia (CDSS) sum score was the primary outcome. Latent growth curve (LGCM) and Growth Mixture Models (GMM) were conducted. Predictors were the Positive sum score of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), Schizophrenia spectrum/non-spectrum psychoses, gender and being antipsychotic naive at inclusion. We found support for three depression-trajectories, including a high- (14.7%), a low depression-level (69.6%) class and a third depressed class quickly decreasing to a low level (15.7%). Change in CDSS was associated with change in PANSS positive score in all time intervals (4 weeks: b = 0.18, p < 0.001, 3 months: 0.21, p < 0.023, 6 months: 0.43, p < 0.001) and with a diagnosis within schizophrenia spectrum but not with antipsychotic naivety or gender. The schizophrenia-spectrum patients had less depressive symptoms at inclusion (-2.63, p < 0.001). In conclusion, an early responding and a treatment refractory group were identified. The treatment-refractory patients are candidates for enhanced anti-depressive treatment, for which current evidence is limited. The post-psychotic depression group was characterized by depressive symptoms in the acute phase as well. We could not identify differentiating characteristics of the depression trajectories.

Suicidality in schizophrenia spectrum disorders: the relationship to hallucinations and persecutory delusions.

BACKGROUND: Assessment of suicide risk is crucial in schizophrenia and results concerning risk contributed by hallucinations and persecutory delusions are inconsistent. We aimed to determine factors associated with suicidal ideation and plans at the time of acute admission in patients suffering from schizophrenia spectrum disorders. METHODS: One hundred and twenty-four patients older than 18 years admitted to an acute psychiatric ward due to psychosis were consecutively included. Predictors of suicidal ideation and suicide plans at the time of admission were examined with multinominal logistic regression and structural equation modelling (SEM). The study design was pragmatic, thus entailing a clinically relevant representation. RESULTS: Depression Odds Ratio (OR) 12.9, Drug use OR 4.07, Hallucinations OR 2.55 and Negative symptoms OR 0.88 significantly predicted Suicidal ideation. Suspiciousness/ Persecution did not. Only Depression and Hallucinations significantly predicted Suicide plans. In the SEM-model Anxiety, Depression and Hopelessness connected Suspiciousness/Persecution, Hallucinations and Lack of insight with Suicidal ideation and Suicide plans. CONCLUSIONS: The study contributes to an increasing evidence base supporting an association between hallucinations and suicide risk. We want to emphasise the importance of treating depression and hallucinations in psychotic disorders, reducing hopelessness while working with insight and reducing drug abuse in order to lower suicide risk. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://www.clinicaltrials.gov/NCT00932529.

Self-harm induced somatic admission after discharge from psychiatric hospital - a prospective cohort study.

BACKGROUND: Few studies have examined rate and predictors of self-harm in discharged psychiatric patients. AIMS: To investigate the rate, coding, timing, predictors and characteristics of self-harm induced somatic admission after discharge from psychiatric acute admission. METHOD: Cohort study of 2827 unselected patients consecutively admitted to a psychiatric acute ward during three years. Mean observation period was 2.3 years. Combined register linkage and manual data examination. Cox regression was used to investigate covariates for time to somatic admission due to self-harm, with covariates changing during follow-up entered time dependently. RESULTS: During the observation period, 10.5% of the patients had 792 somatic self-harm admissions. Strongest risk factors were psychiatric admission due to non-suicidal self-harm, suicide attempt and suicide ideation. The risk was increased throughout the first year of follow-up, during readmission, with increasing outpatient consultations and in patients diagnosed with recurrent depression, personality disorders, substance use disorders and anxiety/stress-related disorders. Only 49% of the somatic self-harm admissions were given hospital self-harm diagnosis. CONCLUSIONS: Self-harm induced somatic admissions were highly prevalent during the first year after discharge from acute psychiatric admission. Underdiagnosing of self-harm in relation to somatic self-harm admissions may cause incorrect follow-up treatments and unreliable register data.

Neurocognitive effectiveness of quetiapine, olanzapine, risperidone, and ziprasidone: a pragmatic, randomized trial.

PURPOSE: Cognitive effects of second generation antipsychotics (SGAs) are indicated in efficacy studies but the generalizability of the results may be limited by rigid designs and selected samples. The aim of this naturalistic, industry-independent study is to investigate whether differential neurocognitive effectiveness can be found among olanzapine, quetiapine, risperidone, and ziprasidone in a clinically relevant sample with psychosis. SUBJECTS AND METHODS: Adult patients acutely admitted to an emergency ward for psychosis were randomized to risperidone, olanzapine, quetiapine or ziprasidone and followed for up to 2 years. Participants were assessed repeatedly using the Positive and Negative Syndrome Scale and a repeatable neurocognitive test battery. RESULTS: A total of 226 patients were included and 171 patients underwent neurocognitive assessments. The sample had a global cognitive performance score at baseline about one standard deviation below that of the general population. The ziprasidone group had the fastest increase in global functioning which was significantly superior to that of the olanzapine group for the entire follow-up period. Before 90 days, the quetiapine group had the fastest increase which was statistically superior to the olanzapine group. DISCUSSION: Ziprasidone and quetiapine demonstrated superiority to olanzapine in increasing global neurocognitive performance in this naturalistic sample.

Time-dependent effect analysis of antipsychotic treatment in a naturalistic cohort study of patients with schizophrenia.

OBJECTIVE: Evidence based treatment of schizophrenia as well as antipsychotic drug utility patterns have changed considerably in recent years and the present study aims to investigate the current level of unplanned hospital readmissions in a cohort of patients with schizophrenia, and to determine the risk-reducing effects of current antipsychotic drug treatment. METHOD: An open cohort study included all consecutively discharged patients with schizophrenia in a 3-year period (n=277). The treatment-dependent variables were entered in a multivariate Cox survival analyses with time to unplanned readmission as the dependent variable. RESULTS: 11.2% of patients were readmitted within 30 days of discharge, and 44.8% were readmitted within 12 months. Antipsychotic monotherapy reduced the risk of readmission by 74.9%. Treatment in CMHC also had a risk-reducing effect. The prescription rate of clozapine in this sample was 10.1%. DISCUSSION: The over-all level of unplanned readmissions was in correspondence with the findings of others. Current antipsychotic drug treatment independently offers strong protection against unplanned readmissions. There may be a potential for further optimalizing antipsychotic drug treatment according to treatment guidelines. CONCLUSIONS: Unplanned readmissions are very common for patients with schizophrenia but antipsychotic drug treatment is associated with a strong risk-reducing effect in this regard.

Positive symptoms and duration of illness predict functional laterality and attention modulation in schizophrenia.

OBJECTIVE: Dichotic listening (DL) performance in schizophrenia, reflecting hemispheric asymmetry and the functional integrity of the left temporal lobe, can vary with clinical characteristics. Previous studies have not taken the co-linearity of clinical variables into account. The aim of the present study was to evaluate the roles of positive symptoms and duration of illness in DL through Structural Equation Modeling (SEM), thus allowing for complex relationships between the variables. METHOD: We pooled patients from four previous DL studies to create a heterogeneous group of 129 schizophrenic patients, all tested with a consonant-vowel syllables DL procedure that included attentional instructions. RESULTS: A model where positive symptoms predicted a laterality component and duration of illness predicted an attention component in DL was confirmed. CONCLUSION: Positive symptoms predicted reduced functional laterality, suggesting involvement of left temporal lobe language processing. Duration of illness predicted impaired attention modulation, possibly reflecting the involvement of frontotemporal networks.

Practice regarding antipsychotic therapy: a cross-sectional survey in two Norwegian hospitals.

Since the introduction of chlorpromazine, an increasing number of drugs have been added to the list of antipsychotics (neuroleptics). These drugs can be further classified as either first-generation antipsychotics (FAPs) or second-generation antipsychotics (SAPs), depending on their ability to antagonize serotonine in addition to dopamine. The efficacy of various drugs is generally equal, whereas both pharmacological profiles and side-effects differ. Antipsychotic drug therapy recommendations are available both in Norway and internationally, and the purpose of this cross-sectional survey was to register the use of these drugs in representative mental hospitals (A and B), and compare our findings to the recommendations. Medical prescriptions were registered, and data further analysed. In hospital A, a total of 149 patients' prescriptions were registered. Antipsychotics were received voluntarily by 117 patients. Eighty-two of these used one antipsychotic drug, and in this group, 65% received SAPs. Antipsychotic combination therapy was received by 35 patients, and was associated with higher prescription rates of both anticholinergics and benzodiazepines. SAPs were not associated with increased use of benzodiazepines, compared to FAPs. Antipsychotics were frequently combined with mood stabilizers and antidepressants. Our findings in hospital A concerning therapy practices of antipsychotics, were confirmed in hospital B, where 64 patients' medical prescriptions were registered. We conclude that FAPs are still commonly prescribed. Antipsychotic combination therapy is used despite of lack of evidence for efficacy, and is associated with increased prescription rates of anticholinergics and benzodiazepines.

Oral dyskinesias and histopathological alterations in substantia nigra after long-term haloperidol treatment of old rats.

The pathophysiologic basis of tardive dyskinesia remains unclear, but several lines of evidence suggest that persistent neuronal changes in the basal ganglia produced by oxidative stress or glutamate toxicity may play a role, especially in the elderly. In the present study we examined whether histopathological alterations in substantia nigra are related to oral dyskinesia in a rodent model of tardive dyskinesia. Haloperidol decanoate (38 mg/kg/4 weeks) was administered to young (8 weeks) and old (38 weeks) rats for a total period of 28 weeks, and the development of vacuous chewing movements (VCM) was observed. Rats with high and low levels of VCM and saline-treated controls were analyzed for histopathological alterations. Reduced nerve cell number and atrophic neurons were prominent features in the substantia nigra of old rats with high levels of VCM. Some alterations were also present in the substantia nigra of the old rats with low levels of VCM and young rats with high VCM levels, but these were significantly less affected than the high VCM rats. These results show that the development of haloperidol-induced oral dyskinesias in old rats is associated with histopathological alterations in the substantia nigra. This suggests that nigral degeneration induced by neuroleptics may contribute to the development of persistent VCM in rats and possibly irreversible tardive dyskinesia in humans.

Oral dyskinesias and morphological changes in rat striatum during long-term haloperidol administration.

RATIONALE: Neuroleptic-induced oral dyskinesias in rats, a putative analogue to human tardive dyskinesia, may be due to increased glutamate release within the striatum. This may lead to excitotoxic degeneration and, as a consequence, persistent motor side effects. OBJECTIVES: To investigate whether alterations in glutamatergic synapses within the striatum are associated with the development of neuroleptic-induced oral dyskinesia. METHODS: Haloperidol was administered for 20 weeks, and rats with high and low levels of vacuous chewing movements (VCM) were analyzed for morphological changes with electron microscopy at three time points. RESULTS: At week 8, the high VCM rats had a larger nerve terminal area and lower density of nerve terminal glutamate immunoreactivity than the other groups. After 18 weeks of treatment, the nerve terminal area was increased relative to controls in both the high and low VCM groups. After discontinuation of treatment, there were no significant morphological differences between the groups, but the level of VCM was still significantly increased in the high VCM group. CONCLUSIONS: These results show that striatal glutamatergic transmission is affected during haloperidol treatment and the nerve terminal area and the density of nerve terminal glutamate immunoreactivity are important in determining the VCM response to haloperidol treatment. This indicates that increased glutamatergic synaptic activity in the striatum contributes to the development of human tardive dyskinesia.

Effects of dihydroergotamine on intracranial pressure, cerebral blood flow, and cerebral metabolism in patients undergoing craniotomy for brain tumors.

In a search for a nonsurgical intervention to control intracranial hypertension during craniotomy, the authors studied the effects of dihydroergotamine on mean arterial blood pressure (MABP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), cerebral blood flow (CBF), and cerebral metabolism in patients who underwent craniotomy for supratentorial brain tumors. Twenty patients were randomized to receive either dihydroergotamine 0.25 mg intravenously or placebo as a bolus dose during craniotomy. Anesthesia was induced with thiopental/fentanyl/atracurium, and maintained with isoflurane/N2O/fentanyl at normocapnia. After removal of the bone flap and exposure of intact dura, ICP was measured subdurally and dihydroergotamine/placebo was administered. Intracranial pressure and MABP were measured continuously. Cerebral blood flow (after intravenous administration of 133Xe) and arteriojugular venous difference of oxygen (AVDO2) were measured before, and 30 minutes after, dihydroergotamine/placebo administration. Cerebral metabolic rate of oxygen (CMRO2) was calculated. After administration of dihydroergotamine, a significant increase in MABP from 74 to 87 mm Hg (median) and CPP from 65 to 72 mm Hg (median) were found. Simultaneously to the increase in MABP, a significant increase in ICP from 9.5 to 11.5 mm Hg (median) was disclosed, whereas no significant differences in CBF, AVDO2, or CMRO2 were found. Intracranial pressure was significantly higher after dihydroergotamine than after placebo. In conclusion, no ICP decreasing effect of a bolus dose of dihydroergotamine was found when administered to patients with brain tumors during isoflurane/N2O anesthesia. Corresponding increases in MABP and ICP suggest that abolished cerebral autoregulation might explain why dihydroergotamine was associated with an ICP increase.

The DaNeX study of embryonic mesencephalic, dopaminergic tissue grafted to a minipig model of Parkinson's disease: preliminary findings of effect of MPTP poisoning on striatal dopaminergic markers.

A multicenter study is under way to investigate the efficacy of allografting of embryonic mesencephalic neurons in a pig model of Parkinson's disease. We have first established that a stable parkinsonian syndrome can be established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of adult male Göttingen minipigs. We are now using positron emission tomography (PET) methods for testing the physiological responses to MPTP intoxication and the time course of the response to several treatment strategies. We now report preliminary results obtained in 11 pigs employed in the initial phase of the study; the completed study shall ultimately include 30 pigs. Animals were randomly assigned to one of five groups: 1) Control, 2) MPTP intoxication, 3) MPTP intoxication followed by allograft, 4) MPTP intoxication followed by allograft with immunosuppression, and 5) MPTP intoxication followed by allograft with immunosuppression and co-grafting of immortalized HiB5 cells, which had been manipulated to secrete glia cell line-derived neurotrophic factor (GDNF) (approximately 2 ng GDNF/h/10(5) cells). MPTP was administered (1 mg/kg/day, SC) for 7-10 days until the pigs had developed mild parkinsonian symptoms of muscle rigidity, hypokinesia, and impaired coordination, especially of the hind limbs. Approximately 2 weeks after the last MPTP dose, animals received a T1-weighted magnetic resonance imaging (MRI) scan, and a series of dynamic PET recordings. After the first series of PET scans, four grafts of porcine embryonic mesencephalic tissue (E28 days) were placed in each striatum of some MPTP-intoxicated pigs, using MRI-based stereotactic techniques. Immunosuppression of some animals with cyclosporin and prednisolone began just prior to surgery. Two more series of PET scans were performed at 4-month intervals after surgery. After the last scans, pigs were killed and the brains were perfused for unbiased stereological examination of cytological and histochemical markers in striatum and substantial nigra. The behavioral impairment of the animals (the "Parkinson's score") had been evaluated throughout the 8-month period. Kinetic analysis of the first set of PET scans has indicated that the rate constant for the decarboxylation of FDOPA in catecholamine fibers was reduced by 33% in striatum of the mildly parkinsonian pigs. The rate of association of [11C]NS-2214 to catecholamine uptake sites was reduced by 62% in the same groups of pigs. No significant difference was found in the binding potential of [11C]raclopride to the dopamine D2-like receptors in striatum of the MPTP-intoxicated versus control pigs. These preliminary results are suggestive that the activity of DOPA decarboxylase may be upregulated in the partially denervated pig striatum.

Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia?

Tardive dyskinesia is a serious motor side effect of long-term treatment with neuroleptics, with an unknown pathophysiologic basis. Brain damage and aging are prominent risk-factors, and together with the persistent character of the disorder, it is likely that long-lasting neuronal changes are involved in the pathogenesis. It has been hypothesized that striatal neurodegeneration caused by excitotoxic mechanisms and oxidative stress may play an important role in the development of the disorder, and the scope of the present work is to review the evidence supporting this hypothesis. The rat model of tardive dyskinesia has been used extensively in the field, and the usefulness of this model will be discussed. Neuroleptics are able to induce oxidative stress in vitro and increase striatal glutamatergic activity in rats, which may lead to toxic effects in the striatum. Drugs that block excitotoxicity inhibit the development of persistent oral dyskinesia in the rat model, and impaired energy metabolism leads to increased frequency of oral dyskinesia. There are also signs of altered striatal histology in rats with high frequency of oral dyskinesia. Furthermore, markers of increased oxidative stress and glutamatergic neurotransmission have been found in the cerebrospinal fluid of patients with tardive dyskinesia. In conclusion, several lines of evidence implicate neurotoxic events in the development of neuroleptic induced tardive dyskinesia.

No changes in dopamine D(1) receptor mRNA expressing neurons in the dorsal striatum of rats with oral movements induced by long-term haloperidol administration.

Neuroleptic-induced vacuous chewing movements (VCM) in rats, a putative analogue to tardive dyskinesia in man, may involve degeneration within striatum as well as changes in neurotransmitter and receptor expression. In this study, we measured the expression of dopamine D(1) receptor mRNA by dorsal striatal neurons in rats with high and low level of VCM after treatment with haloperidol for 38 weeks. Both the average integrated density of the in situ hybridization signal and number of cells obtained by the stereological cell counting remained within control level, irrespective of the level of haloperidol-induced oral dyskinesia.

Reduced number of striatal neurons expressing preprosomatostatin mRNA in rats with oral dyskinesias after long-term haloperidol administration.

Neuroleptic-induced oral dyskinesia in rats, a putative analogue to human tardive dyskinesia, may be due to degeneration within the striatum. Using unbiased stereological methods, a decreased number of striatal neurons expressing preprosomatostatin mRNA was observed only in rats that developed pronounced oral dyskinesias after 30 weeks of haloperidol administration. The amount of preprosomatostatin mRNA in each striatal neuron, measured in terms of optical densities of individual neurons, was not affected by haloperidol. A tendency toward a reduction in the number of NADPH-diaphorase positive neurons was observed in rats receiving haloperidol. These results indicate that the mechanism by which neuroleptics induce oral dyskinesias in rats, and perhaps tardive dyskinesia in humans, involves a functional disruption and possibly damage of a subpopulation of interneurons in the striatum.

Coenzyme Q10 does not prevent oral dyskinesias induced by long-term haloperidol treatment of rats.

Tardive dyskinesia (TD) is a debilitating side effect of long-term treatment with neuroleptics with an unclear pathophysiologic basis. It has been proposed that TD may be a result of neuroleptic-induced oxidative stress. To investigate this hypothesis, we studied if neuroleptic-induced oral dyskinesias in rats, a putative analogue to human TD, could be prevented by the antioxidant coenzyme Q10 (CoQ10). Rats received 16 weeks of treatment with haloperidol decanoate (HAL) IM alone or together with orally administered CoQ10, and the behavior was recorded during and after treatment. HAL significantly increased the level of oral dyskinesias, and the increase persisted for 12 weeks after drug withdrawal. Cotreatment with CoQ10 did not attenuate the development of HAL-induced oral dyskinesia. Despite adequate absorption of orally administered CoQ10, shown by the increased serum levels of CoQ10, no increase of either CoQ10 or coenzyme Q9 was detected in the brain. These results suggest that cotreatment with CoQ10 does not inhibit the development of HAL-induced oral dyskinesias in rats, and that further studies seem to be needed in order to clarify the pharmacokinetics of CoQ10 in rats.

The relationship between oral dyskinesias produced by long-term haloperidol treatment, the density of striatal preproenkephalin messenger RNA and enkephalin peptide, and the number of striatal neurons expressing preproenkephalin messenger RNA in rats.

Neuroleptic-induced oral dyskinesias in rats, a putative analogue to human tardive dyskinesia, may be due to excitotoxic degeneration within the striatum. Haloperidol treatment for 34 weeks increased the optical density of preproenkephalin messenger RNA in individual striatal neurons and enkephalin peptide in the neuropil, regardless of the level of oral dyskinesia produced. However, using unbiased stereological methods, an increased number of striatal neurons expressing preproenkephalin messenger RNA was observed only in rats that did not develop pronounced oral dyskinesias during haloperidol treatment. Said in another manner, the haloperidol-treated animals that developed pronounced oral dyskinesias, failed to produce an increase in the number of neurons expressing preproenkephalin messenger RNA. These results indicate that the mechanism by which neuroleptics induce oral dyskinesias in rats, and perhaps tardive dyskinesia in humans, involves a functional disturbance or even damage to a subpopulation of enkephalinergic neurons in the striatum.

Subdural pressure measurement during posterior fossa surgery. Correlation studies of brain swelling/herniation after dural incision with measurement of subdural pressure and tactile estimation of dural tension.

Thirty-two patients with posterior fossa tumours or arteriovenous malformations were subjected to elective craniotomy in the prone position. The intracranial pressure (ICP) was measured by a subdural approach in the open area of the exposed dura. Estimation of dural tension before dural incision and the degree of brain swelling/herniation after opening the dura were correlated with the subdural pressure measured with intact dura. The results indicate that at ICP < 10 mmHg, brain swelling/herniation rarely occurred, while at ICP > or = 10 mmHg some degree of brain swelling/herniation was always present. The neurosurgeon's tactile estimation of dural tension correlated poorly with any tendency to brain swelling/herniation. It is concluded that measurement of subdural pressure is a better predictor of the risk of brain swelling/herniation than the tactile estimation of dural tension during posterior fossa surgery.

Oral Dyskinesias and striatal lesions in rats after long-term co-treatment with haloperidol and 3-nitropropionic acid.

The pathophysiologic basis of tardive dyskinesia remains unclear. It has been proposed that tardive dyskinesia may be a result of excitotoxic neurodegeneration in the striatum caused by a neuroleptic-induced increase in striatal glutamate release and impaired energy metabolism. To investigate this hypothesis, haloperidol decanoate (38 mg/kg/four weeks intramuscularly) and the succinate dehydrogenase inhibitor 3-nitropropionic acid (8 mg/kg/day via subcutaneous osmotic mini-pumps), were administered alone or together for 16 weeks to four-months-old rats. Control rats received sesame oil intramuscularly and had empty plastic tubes subcutaneously. Vacuous chewing movements, a putative analogue to human tardive dyskinesia, were recorded during and after drug treatment. Haloperidol alone, 3-nitropropionic acid alone, and 3-nitropropionic acid+haloperidol treatments induced an increase in vacuous chewing movements. However, vacuous chewing movements were more pronounced and appeared earlier in rats treated with 3-nitropropionic acid+haloperidol. After drug withdrawal, increases in vacuous chewing movements persisted for 16 weeks in the haloperidol alone and 3-nitropropionic acid+haloperidol group and for four weeks in the 3-nitropropionic acid alone group. Brains from each group were analysed for histopathological alterations. Bilateral striatal lesions were present only in rats with high levels of vacuous chewing movements in the 3-nitropropionic acid+haloperidol-treated rats. Nerve cell depletion and astrogliosis were prominent histopathologic features. There was selective neuronal sparing of both large- and medium-sized aspiny striatal neurons. These results suggest that mild mitochondrial impairment in combination with neuroleptics results in striatal excitotoxic neurodegeneration which may underlie the development of persistent vacuous chewing movements in rats and possibly irreversible tardive dyskinesia in humans.

Correlation of vacuous chewing movements with morphological changes in rats following 1-year treatment with haloperidol.

Long-term treatment with the typical antipsychotic drug, haloperidol, can lead to a sometimes irreversible motor disorder, tardive dyskinesia (TD). It has been hypothesized that increased release of glutamate due to prolonged neuroleptic drug treatment may result in an excitotoxic lesion in specific neuronal populations within the basal ganglia, leading to TD. We reported that treatment with haloperidol for 1 month results in an increase in the mean percentage of striatal asymmetric synapses containing a perforated postsynaptic density (PSD) and that these synapses are glutamatergic. Using quantitative immunocytochemistry, we found that depending on how long the animals had been off haloperidol following subchronic (30 d) treatment, there was either a decrease (1 day off) or increase (3-4 days off) in the density of glutamate immunolabeling within the presynaptic terminals of synapses with perforated PSDs. Using a rat model for TD, animals in the current study were treated for 1 year with haloperidol and spontaneous oral dyskinesias (i.e. vacuous chewing movements, VCMs) were recorded. In these long-term treated animals we wanted to determine if there was a correlation between glutamate function, as measured by changes in synapses with perforated PSDs and the density of nerve terminal glutamate immunoreactivity, and VCM behavior. In drug treated rats which demonstrated either a high or low rate of VCMs, there was a significant increase in the mean percentage of asymmetric synapses in the dorsolateral striatum with perforated PSDs in both haloperidol-treated groups compared to vehicle-treated rats. There was a small but significant increase in the density of glutamate immunolabeling within striatal nerve terminals of the high VCM group compared to the low VCM group. There was, however, no difference in the density of glutamate immunolabeling between the high VCM group compared to the vehicle-treated animals. One reason for this lack of difference was partially due to a significant increase in nerve terminal area within the high VCM group compared to either the low VCM- or vehicle-treated groups. The larger nerve terminal size in the high VCM group may be due to a small but sustained increase in glutamate neurotransmitter release with the ability of the terminal to maintain its supply of glutamate, while the terminals in the low VCM group showed evidence of glutamate depletion. This finding would be consistent with the hypothesis that increased glutamatergic activity may be associated with TD.