Systemic illness moderates the impact of N-acetyl cysteine in bipolar disorder.

OBJECTIVES: Bipolar disorder (BD) is intricately associated with chronic clinical conditions. Medical comorbidity is not only more prevalent in mood disorders, but is associated with increased costs, cognitive impairment and, ultimately, premature mortality. Oxidative stress and inflammation may mediate part of this association. To further investigate the association between medical comorbidity status and clinical improvement with adjuvant N acetyl cysteine (NAC) in the context of a placebo-controlled trial. METHODS: Placebo-controlled randomized clinical trial assessing the effect of NAC over 24 weeks. Symptomatic and functional outcomes were collected over the study period. Medical comorbidities were self-reported, and we took special interest in cardiovascular and endocrine conditions. We evaluated change from baseline to endpoint and the interaction between change and reported medical comorbidities. RESULTS: Fifty-one percent of patients reported have a cardiovascular or endocrine comorbidity. Although not found for depressive symptoms or quality of life, a significant interaction between medical comorbidity and change scores was consistently found for all functional outcomes. This indicated an advantage of NAC over placebo in those with a clinical comorbidity. CONCLUSION: Systemic illness moderated only the effect of NAC on functioning, not on depression. Demonstrating an improvement in functional outcomes with an agent that modulates redox and inflammatory pathways, this study lends empirical support to the idea that medical and psychiatric comorbidity are additive in contributing to allostatic states. One intriguing possibility is that comorbid clinical illness could be a marker for more severe oxidative stress states--and thus guide antioxidant use--in BD.

N-acetyl cysteine add-on treatment for bipolar II disorder: a subgroup analysis of a randomized placebo-controlled trial.

BACKGROUND: The evidence base for the pharmacological treatment of bipolar II disorder is limited. In bipolar disorder, there is evidence for glutathione depletion and increased oxidative stress, as well as dysregulation of glutamate; N-acetyl cysteine (NAC) has effects on both of these systems. Add-on NAC has been shown to have a significant benefit on depressive symptoms in a randomized placebo-controlled trial. In this report, we explore the effects of this compound in a subset of patients with bipolar II disorder from that trial. METHODS: Individuals were randomized to NAC or placebo in addition to treatment as usual, in a double-blind fashion. Mood and functional outcomes were assessed up to 24 weeks of treatment. RESULTS: Fourteen individuals were available for this report, seven in each group. Six people achieved full remission of both depressive and manic symptoms in the NAC group; this was true for only two people in the placebo group (χ(2)=4.67, p=0.031). LIMITATIONS: Subgroup analyses in a small subsample of patients. Not all participants had elevated depression scores at baseline. CONCLUSION: Notwithstanding all the limitations that subgroup analysis of trials carry, this data could serve as a hypothesis-generating stimulus for further clinical trials of pharmacologic treatment for bipolar II depression.

A role for glutathione in the pathophysiology of bipolar disorder and schizophrenia? Animal models and relevance to clinical practice.

The tripeptide, glutathione (gamma-glutamylcysteinylglycine) is the primary endogenous free radical scavenger in the human body. When glutathione (GSH) levels are reduced there is an increased potential for cellular oxidative stress, characterised by an increase and accruement of reactive oxygen species (ROS). Oxidative stress has been implicated in the pathology of schizophrenia and bipolar disorder. This could partly be caused by alterations in dopaminergic and glutamatergic activity that are implicated in these illnesses. Glutamate and dopamine are highly redox reactive molecules and produce ROS during normal neurotransmission. Alterations to these neurotransmitter pathways may therefore increase the oxidative burden in the brain. Furthermore, mitochondrial dysfunction, as a source of oxidative stress, has been documented in both schizophrenia and bipolar disorder. The combination of altered neurotransmission and this mitochondrial dysfunction leading to oxidative damage may ultimately contribute to illness symptoms. Animal models have been established to investigate the involvement of glutathione depletion in aspects of schizophrenia and bipolar disorder to further characterise the role of oxidative stress in psychopathology. Stemming from preclinical evidence, clinical studies have recently shown antioxidant precursor treatment to be effective in schizophrenia and bipolar disorder, providing a novel clinical angle to augment often suboptimal conventional treatments.

Emotional prosodic processing in auditory hallucinations.

Deficits in emotional prosodic processing, the expression of emotions in voice, have been widely reported in patients with schizophrenia, not only in comprehending emotional prosody but also expressing it. Given that prosodic cues are important in memory for voice and speaker identity, Cutting has proposed that prosodic deficits may contribute to the misattribution that appears to occur in auditory hallucinations in psychosis. The present study compared hallucinating patients with schizophrenia, non-hallucinating patients and normal controls on an emotional prosodic processing task. It was hypothesised that hallucinators would demonstrate greater deficits in emotional prosodic processing than non-hallucinators and normal controls. Participants were 67 patients with a diagnosis of schizophrenia or schizoaffective disorder (hallucinating=38, non-hallucinating=29) and 31 normal controls. The prosodic processing task used in this study comprised a series of semantically neutral sentences expressed in happy, sad and neutral voices which were rated on a 7-point Likert scale from sad (-3) through neutral (0) to happy (+3). Significant deficits in the prosodic processing tasks were found in hallucinating patients compared to non-hallucinating patients and normal controls. No significant differences were observed between non-hallucinating patients and normal controls. In the present study, patients experiencing auditory hallucinations were not as successful in recognising and using prosodic cues as the non-hallucinating patients. These results are consistent with Cutting's hypothesis, that prosodic dysfunction may mediate the misattribution of auditory hallucinations.

Measurement of dopamine D2-like receptors in postmortem CNS and pituitary: differential regional changes in schizophrenia.

In situ radioligand binding with autoradiography and anti-human dopamine D(2) receptor antibodies with Western blots have been used to measure the density of dopamine D(2)-like receptors in the caudate-putamen and pituitary from schizophrenic subjects who did or did not have residual antipsychotic drugs in their tissue at death. There was a significant decrease in the Ki for haloperidol displaceable [(125)I]iodosulpride binding in the pituitary (p < 0.01) and caudate-putamen (p < 0.05) from subjects with schizophrenia with residual drugs in their tissue. There was a significant decrease in the density of [(125)I]iodosulpride in the pituitary (p < 0.001) and a strong trend to a decrease in binding in the caudate-putamen (p = 0.055) from subjects with schizophrenia. By contrast, [(3)H]spiperone binding was decreased in the caudate-putamen (p < 0.05) with a trend to decreased binding in the pituitary (p = 0.07) from subjects with schizophrenia. There was no difference in the density of dopamine D(2) receptors in the caudate-putamen from subjects with schizophrenia (p = 0.31). All the findings on receptor densities were independent of drug status. [(125)I]iodosulpride binds to the dopamine D(2&3) receptors. We have shown that there is no change in the dopamine D(2) receptor in the caudate-putamen from subjects with schizophrenia and therefore, these data would be consistent with there being a decrease in the dopamine D(3) in the caudate-putamen from subjects with schizophrenia. Since dopamine D(3) receptors are absent or present at low concentrations in the pituitary, our data would suggest the dopamine D(2) receptor is decreased in that tissue from schizophrenic subjects.

From pharmacotherapy to pathophysiology: emerging mechanisms of apolipoprotein D in psychiatric disorders.

Apolipoprotein D (apoD) is an atypical plasma apolipoprotein and, based on its primary structure, it is a member of the lipocalin protein superfamily. Lipocalins have been extensively used as disease markers and, accordingly, apoD has become increasingly recognized as an important factor in the pathology of human neurodegenerative and neuropsychiatric disorders. ApoD expression is increased in the plasma and brains of subjects with schizophrenia and bipolar disorder, suggesting that it acts as a marker for disease pathology. ApoD also exhibits complex regulation by antipsychotic drug treatment and may represent a distinguishing mechanism of typical versus atypical drugs. The precise role of apoD in the CNS and disease remains to be elucidated, but recent findings have suggested that it plays an important role in the regulation of arachidonic acid signaling and metabolism providing further support for phospholipid membrane pathology in schizophrenia.

Decreased phorbol ester binding in the parahippocampal gyrus from subjects with schizophrenia is not associated with changes in protein kinase C.

Combining in situ radioligand binding with autoradiography, we previously identified a reduction of [(3)H]phorbol 12,13-dibutyrate binding in the parahippocampal gyrus from schizophrenic subjects. To determine whether these changes were due to decreases in the level of protein kinase C, we measured [(3)H]phorbol 12,13-dibutyrate binding, levels of the protein kinase C isoforms alpha, beta, delta, epsilon, gamma, eta and theta, as well as protein kinase C activity in crude particulate membranes from parahippocampal gyri of 15 schizophrenic and 15 control subjects. There was a significant decrease in the density (mean +/- SEM: 6.56 +/- 0.73 pmol mg(-1) vs 9.68 +/- 1.22 pmol mg(-1); P < 0.05) and affinity (mean K(D) +/- SEM: 4.64 +/- 0.34 nM vs 2.95 +/- 0.35 nM; P < 0.005) of [(3)H]phorbol 12,13-dibutyrate binding in homogenates from schizophrenic subjects. There were no significant changes in levels of the protein kinase C isoforms which are known to bind phorbol esters or in the activity of protein kinase C in membranes from schizophrenic subjects. These results suggest that there are changes in molecules capable of binding [(3)H]phorbol 12,13-dibutyrate, other than protein kinase C, in the parahippocampal gyrus from subjects with schizophrenia.

Extended treatment with typical and atypical antipsychotic drugs differential effects on the densities of dopamine D2-like and GABAA receptors in rat striatum.

In situ radioligand binding and quantitative autoradiography have been used to measure the density of striatal D1-like, D2-like, and GABAA receptors in rats treated with haloperidol at 0.01 or 0.1 mg/kg/ day or chlorpromazine, olanzapine or clozapine at 0.1 or 1.0 mg/kg/day for 1, 3 or 7 months. [3H]SCH23390 binding to D1-like receptors was not changed by any drug treatments. There were significant increases in [3H]nemonapride binding to D2-like receptors at different time points due to treatment with haloperidol, chlorpromazine and olanzapine. By contrast, treatment with clozapine and olanzapine caused a time-dependent decrease in [3H]muscimol binding to the GABAA receptor. These data suggest that treatment with atypical antipsychotic drugs, but not typical antipsychotic drugs, affect striatal GABAergic neurons. In addition, it would appear that clozapine might be unique in that it does not increase dopamine-D2 like receptor density at doses which would be predicted to have antipsychotic effects in humans. The extent to which such changes are involved in the therapeutic effects of drugs such as olanzapine and clozapine remains to be determined.

Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: a study of Brodmann's areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment.

OBJECTIVE: Aberrant cholinergic inputs and synaptic neurotransmission in the prefrontal cortex induce cognitive impairment, which is a central feature of schizophrenia. Postsynaptic excitatory muscarinic cholinergic M(1) and M(4) receptors are the major cholinoceptive targets in the prefrontal cortex and hence may be involved in the pathology and/or pharmacotherapeutics of schizophrenia. METHOD: Using quantitative autoradiography, the authors analyzed the binding of the M(1)/M(4) receptor selective antagonist [(3)H]pirenzepine in prefrontal cortex (Brodmann's areas 8, 9, 10, and 46) from schizophrenia patients who had (N=6) or had not (N=11) been treated with the anticholinergic agent benztropine mesylate and from normal comparison subjects (N=20). Moreover, preliminary studies of [(3)H]pirenzepine binding in rat frontal cortex following administration of antipsychotic drugs or benztropine mesylate were performed. RESULTS: Relative to those of comparison subjects, the mean levels of [(3)H]pirenzepine binding were significantly lower in Brodmann's areas 9 and 46 of the schizophrenia patients not treated with benztropine mesylate (18% lower in Brodmann's area 9 and 21% lower in Brodmann's area 46) and in all four examined regions of the patients who had received benztropine (51%-64% lower). Antipsychotic or anticholinergic drugs tended to increase or have no effect on the density of [(3)H]pirenzepine-labeled receptors in rat frontal cortex. CONCLUSIONS: Because M(1) and M(4) receptors are critical to the functions of prefrontal cortical acetylcholine, the present findings suggest a functional impairment in cholinergic neurotransmission in schizophrenia and the possibility that muscarinic receptors are involved in the pharmacotherapeutics of the disorder.

Stability of olfactory identification deficits in neuroleptic-naive patients with first-episode psychosis.

OBJECTIVE: Olfactory identification deficits and their relationship to negative symptoms in patients with schizophrenia were examined in patients with recent-onset psychosis, the majority of whom were neuroleptic naive. METHOD: Seventy-four inpatients with a first episode of psychosis (27 with schizophrenia or schizophreniform disorder, nine with schizoaffective disorder, 17 with affective psychoses, and 21 with other psychoses), 49 of whom had not received antipsychotic medication, were compared to 38 age- and gender-matched normal subjects. Olfactory identification ability was assessed with the University of Pennsylvania Smell Identification Test. Forty patients and 13 comparison subjects were reassessed at 6 months to examine whether olfactory deficits were specific to schizophrenia or schizophreniform disorder and were stable over time. RESULTS: At baseline, the patients had significant impairment in olfactory identification ability compared to the normal subjects. This difference persisted after controlling for gender, premorbid or current IQ, smoking history, cannabis use, or the effects of medication. Diagnostic subgroups did not differ in olfactory identification ability. The deficits remained stable at 6-month follow-up and were associated with negative symptoms at both time points. No relationship was found between olfactory identification ability and length of either untreated psychosis or illness prodrome. CONCLUSIONS: Impairment in olfactory identification ability was apparent from the outset of psychotic illness and was not specific to schizophrenia or schizophreniform disorder. No change in the degree of this deficit was found after patients were stabilized and had responded to medication. The deficit could not be explained by peripheral factors that might contribute to olfactory identification ability, suggesting that it reflects central mechanisms.

A proposed pathological model in the hippocampus of subjects with schizophrenia.

1. The hippocampal formation plays an important role in the normal functioning of the brain, being implicated in cognition and sensory gating, both of which are affected in schizophrenia. The hippocampal formation receives information from the association cortices, which is processed by glutamatergic transmission within the hippocampus. Dopamine, noradrenaline, 5-hydroxytryptamine (5-HT), acetylcholine and GABA, all of which have been proposed to play a role in the neurobiology of schizophrenia, can affect this transmission. 2. The advent of the 'atypical' antipsychotics, with their broad pharmacological spectra and improved therapeutic outcome, has revitalized research into neurotransmitter dysfunction other than that of dopamine. In particular, there has been interest in the serotonergic and cholinergic systems within the hippocampal formation because these are two of the transmitter systems targeted by clozapine and olanzapine. 3. From the study of these systems, using tissue obtained postmortem from subjects with schizophrenia, we propose that there is a hyperserotonergic state in the hippocampal formation of some subjects with schizophrenia caused by a conformational change in the 5-HT transporter. The model we propose allows us to construct further studies that will test the consequences of such a hyperserotonergic state in the hippocampal formation. This model has the potential to open new avenues in schizophrenia research.

Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation.

BACKGROUND: Acetylcholine is important to hippocampal function, including the processes of learning and memory. Patients with schizophrenia show impaired learning and memory and hippocampal dysfunction. Thus, acetylcholinergic systems may be primarily or secondarily disrupted in the hippocampal formation of schizophrenic patients. The present study tested the hypothesis that [(3)H]pirenzepine-labeled muscarinic cholinergic receptor levels are altered in the hippocampal formation of patients with schizophrenia. METHODS: We have used quantitative autoradiography to measure [(3)H]pirenzepine binding to M(1) and M(4) receptors in the hippocampal formation from 15 schizophrenic and 18 nonschizophrenic subjects. RESULTS: The mean density of [(3)H]pirenzepine binding was reduced in all regions studied, including the dentate gyrus, subdivisions of Ammon's Horn (CA1-CA4), subiculum, and the parahippocampal gyrus, of the schizophrenic cohort. Moreover, unlike controls, there was no significant variation between the mean levels of [(3)H]pirenzepine binding across the subregions of the hippocampal formation from schizophrenic subjects. CONCLUSIONS: These findings provide support for a possible involvement of the muscarinic cholinergic system in the pathology and/or treatment of schizophrenia.

Muscarinic1 and 2 receptor mRNA in the human caudate-putamen: no change in m1 mRNA in schizophrenia.

Studies using tissue obtained at autopsy suggest that changes in cholinergic neurons could be important in the pathology of schizophrenia.1-4 We have previously reported a decrease in [3H]pirenzepine binding5 and [3H]AF-DX 384 binding6 to caudate-putamen (CP) from subjects who had schizophrenia. Under the conditions chosen, [3H]pirenzepine would predominately bind to muscarinic1 (M1) and muscarinic4 (M4) receptors,7whereas [3H]AF-DX 384 would mainly bind to muscarinic2 (M2) and M4 receptors.8 Given the relative concentrations of M1, M2 and M4 receptors in the human CP and the magnitude of the decreases in radioligand binding in schizophrenia, our results most likely reflected a change in the density of M1 and M2 receptors in the CP from the schizophrenic subjects. In situ hybridisation has now been used to determine levels of m1 and m2 mRNA in CP from 14 schizophrenic and 16 control subjects previously used for radioligand binding. m2 mRNA in the CP from the schizophrenic and control subjects was below the sensitivity of in situhybridisation. There was no difference in the levels of m1 mRNA in CP from schizophrenic and control subjects (mean +/- SEM: 103 +/- 16 vs106 +/- 17 fmol [35S]oligonucleotide probe g-1estimated tissue equivalents, P = 0.91). In conclusion, data from our radioligand binding studies show decreases in [3H]pirenzepine binding that are likely to reflect a decrease in the density of M1 receptors in CP from schizophrenic subjects. Our data in this study show the absence of a concomitant change in mRNA coding for that receptor.

Central auditory processing in patients with auditory hallucinations.

OBJECTIVE: Data from a full assessment of auditory perception in patients with schizophrenia were used to investigate whether auditory hallucinations are associated with abnormality of central auditory processing. METHOD: Three groups of subjects participated in auditory assessments: 22 patients with psychosis and a recent history of auditory hallucinations, 16 patients with psychosis but no history of auditory hallucinations, and 22 normal subjects. Nine auditory assessments, including auditory brainstem response, monotic and dichotic speech perception tests, and nonspeech perceptual tests, were performed. Statistical analyses for group differences were performed using analysis of variance and Kruskal-Wallis tests. The results of individual patients with test scores in the severely abnormal range (more than three standard deviations from the mean for the normal subjects) were examined for patterns that suggested sites of dysfunction in the central auditory system. RESULTS: The results showed significant individual variability among the subjects in both patient groups. There were no group differences on tests that are sensitive to low brainstem function. Both patient groups performed poorly in tests that are sensitive to cortical or high brainstem function, and hallucinating patients differed from nonhallucinating patients in scores on tests of filtered speech perception and response bias patterns on dichotic speech tests. Six patients in the hallucinating group had scores in the severely abnormal range on more than one test. CONCLUSIONS: Hallucinations may be associated with auditory dysfunction in the right hemisphere or in the interhemispheric pathways. However, comparison of results for the patient groups suggests that the deficits seen in hallucinating patients may represent a greater degree of the same types of deficits seen in nonhallucinating patients.

A multicentre, double-blind, randomized comparison of quetiapine (ICI 204,636, 'Seroquel') and haloperidol in schizophrenia.

BACKGROUND: Quetiapine (ICI 204,636, 'Seroquel') is a new atypical antipsychotic agent with a similar binding profile to the original atypical antipsychotic, clozapine. Its clinical efficacy has already been demonstrated at multiple fixed doses (150-750 mg/day) and has been suggested to be comparable with haloperidol (12 mg/day). METHODS: This international, 6-week, multicentre, double-blind, randomized, parallel-group trial compared quetiapine with haloperidol (455 mg and 8 mg mean total daily doses, respectively) in 448 hospitalized patients with acute exacerbation of chronic or subchronic schizophrenia (DSM-III-R), in order to establish their equivalence in terms of efficacy, and the nature of their tolerability profiles, especially in terms of extrapyramidal symptoms (EPS) and serum prolactin levels. RESULTS: Both quetiapine and haloperidol produced a clear reduction in the Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression (CGI) Severity of Illness and Global Improvement scores. At day 42, the PANSS total score was reduced by -18.7+/-1.63 in the quetiapine group, and -22.1+/-1.63 in the haloperidol group (P = 0.13, between-treatment). Quetiapine was better tolerated than haloperidol in terms of EPS as demonstrated by the significant differences in the Simpson Scale and Abnormal Involuntary Movement Scale scores (P < 0.05). Although patients in both groups had elevated serum prolactin concentrations at baseline, mean serum prolactin concentration decreased (by 16.5 microg/l) in quetiapine-treated patients, yet increased (by 5.9 microg/l) in patients treated with haloperidol. CONCLUSION: Quetiapine is an effective and well tolerated antipsychotic of comparable efficacy to haloperidol and lacks the latter compound's effect on prolactin and EPS.

No correlation between A(-1438)G polymorphism in 5-HT2A receptor gene promoter and the density of frontal cortical 5-HT2A receptors in schizophrenia.

The A(-1438)G promoter polymorphism of the 5-hydroxytryptamine 2a receptor (5-HT2AR) gene and its influence on the cortical density of 5-HT2AR was studied using brain tissue donated at autopsy from 58 schizophrenic and 64 non-schizophrenic subjects. A linkage between genotypes for the A(-1438)G and a T102C polymorphic site identified in a previous study was observed. Our data suggest no association of the A(-1438)G polymorphism with schizophrenia and no effect of the promoter genotype upon 5-HT2AR densities in either the schizophrenic or non-schizophrenic groups.

Changes in serotonin2A and GABA(A) receptors in schizophrenia: studies on the human dorsolateral prefrontal cortex.

Having shown a decrease in serotonin2A receptors in the dorsolateral prefrontal cortex (DLPFC) from schizophrenic subjects, we have now determined if this change was reflective of widespread changes in neurochemical markers in DLPFC in schizophrenia. In Brodmann's area (BA) 9 from 19 schizophrenic and 19 control subjects, we confirmed a decrease in the density of [3H]ketanserin binding to serotonin2A receptors in tissue from the schizophrenic subjects [39 +/- 3.3 vs. 60 +/- 3.6 fmol/mg estimated tissue equivalents (ETE); p < 0.005]. In addition, the density of [3H]muscimol binding to GABA(A) receptors was increased in the schizophrenic subjects (526 +/- 19 vs. 444 +/- 28 fmol/mg ETE; p < 0.02). [3H]YM-09151-2, N-[1-(2-thienyl)cyclohexyl]-3,4-[3H]piperidine, [3H]SCH 23390, [3H]mazindol, and N(G)-nitro-L-[3H]arginine binding to BA 9 did not differ between groups, and there was no specific binding of [3H]raclopride or 7-hydroxy-2-(di-n-[3H]propylamino)tetralin to BA 9 from either cohort of subjects. This suggests the density of dopamine D1-like and NMDA receptors, the dopamine transporter, and nitric oxide synthase activity are not altered in BA 9 from schizophrenic subjects. The selective nature of the changes in serotonin2A and GABA(A) receptors in DLPFC could indicate that these changes are involved in the pathology of schizophrenia.

Steady state visually evoked potential correlates of auditory hallucinations in schizophrenia.

This study attempted to localize regions of brain electrical activity associated with the onset of auditory hallucinations. Changes in Steady State Visually Evoked Potential (SSVEP) topography associated with the onset of spontaneous auditory hallucinations was studied in eight schizophrenic patients. The SSVEP elicited by a spatially uniform sinusoidally varying visual flicker was recorded using a 64-channel electrode helmet. A large and significant decrease in SSVEP latency in the right temporo/parietal region occurred in the second prior to the report of auditory hallucinations. A control task with matching motor movements produced no significant decrease in SSVEP latency in the same right temporo/parietal location. This finding suggests that activity of fine temporal resolution in the neural networks in the right temporo/parietal area may be implicated in the genesis of auditory hallucination, in conformity with certain neuropsychological theories.

Clozapine treatment in Australia: a review of haematological monitoring.

BACKGROUND: Clozapine is an atypical antipsychotic drug indicated for patients with schizophrenia in whom traditional antipsychotic drugs (such as haloperidol or the phenothiazines) are ineffective, or in those who experience intolerable adverse effects. Clozapine treatment may be complicated by the development of life-threatening agranulocytosis, so regular haematological monitoring is required. OBJECTIVES: To determine the incidence of clozapine-induced agranulocytosis in Australia and the importance of monitoring white blood cell counts in patients treated with clozapine. DESIGN: Review of haematological monitoring for the first three years (June 1993-July 1996) of operation of the Australian Clozaril (clozapine; Novartis Australia) Patient Monitoring System (CPMS) central database. RESULTS: In the 4061 patients prospectively monitored by the CPMS, the incidence of agranulocytosis, neutropenia and leukopenia combined was 2.6% (n = 104); the incidence of agranulocytosis was 0.9% (n = 37). So far there have been no deaths in Australia from the complications of clozapine-induced agranulocytosis. CONCLUSION: The incidence of agranulocytosis and neutropenia associated with clozapine use in Australia is similar to that in the rest of the world. Monitoring the white blood cell counts of patients being treated with clozapine ensures minimal risk to patients who develop agranulocytosis.