Discontinuation of clozapine: a 15-year naturalistic retrospective study of 320 patients.

OBJECTIVE: Clozapine is underutilized in the management of treatment-resistant schizophrenia. To understand contributing factors, we analyzed the frequency and causes of clozapine discontinuations that occurred over a 15-year period in a clinical setting. METHOD: Data were extracted from computerized records and from mandatory termination reports for discontinuation events 1993-2007. The reasons for termination were analyzed. RESULTS: Over half of the patients (n = 183/320; 57%) had at least one discontinuation (median time 609 days). The two most common causes for discontinuation were non-adherence (35%) and side-effects (28%). Hematological side-effects accounted for 45% of all side-effect associated discontinuations; most such patients remained eligible for clozapine treatment, and a significant fraction remained on clozapine after rechallenge. Central nervous system side-effects accounted for 35% of side-effect induced discontinuations. General factors significantly associated with discontinuation were African American race, older age at initiation of clozapine and less improvement in psychiatric symptoms. CONCLUSION: In addition to anticipating and addressing causes of non-adherence, psychiatrists should consider clozapine rechallenge in eligible patients and implement measures to mitigate clozapine-associated sedation, seizures, and other side-effects. Future studies should particularly address why African American and older patients may be more likely to discontinue clozapine.

Prefrontal cortical and hippocampal modulation of haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat.

Effects of prefrontal cortical or hippocampal excitotoxic lesions on behavioral parameters related to dopaminergic transmission in the basal ganglia were investigated in the rat. We examined haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors after ibotenic acid lesions of the medial prefrontal cortex (MPFC), dorsal (DH), or ventral hippocampus (VH) in adult rats. Haloperidol-induced (1 mg/kg) catalepsy was decreased in rats with either MPFC or VH but not DH lesions. While both DH and VH lesioned animals demonstrated a reduction in apomorphine-induced (0.75 mg/kg) stereotypic behaviors, the VH lesioned animals also showed an enhancement of locomotor activity. MPFC lesioned rats tended towards potentiation of stereotypic behaviors and reduced locomotion after apomorphine administration. These data indicate that loss of prefrontal cortical or hippocampal modulation leads to an enhancement of DA transmission within the basal ganglia, though the pattern of augmentation depends on the area lesioned.

Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia.

The constellation of major phenomena associated with schizophrenia (e.g., postpubertal onset, congenital hippocampal area damage, cortical functional deficits, limbic dopamine (DA) dysregulation, and vulnerability to stress) have been difficult to explain with a unitary animal model. Although it has been shown that rats develop increased mesolimbic DA transmission and reduced cortical DA turnover following adult excitotoxic lesions of the ventral hippocampus (VH), the implications of early developmental VH lesions are not known. To determine the developmental sequelae of such changes, we produced ibotenic acid lesions of the ventral hippocampal formation in rats on the 7th day after birth (PD7). Motor activity in a novel environment, after saline injection and after d-amphetamine administration were similar in control and lesioned rats at PD35. However, in early adulthood, at PD56, animals with the hippocampal lesion were hyperactive in each of these conditions. The emergence of the hyperactivity at PD56 could be prevented by pretreatment with haloperidol. Moreover, rats lesioned as neonates, in contrast to a similar lesion induced in adult animals, were also hyperresponsive to stress evaluated with a swim test. This latter effect is analogous to that seen after adult lesions of the medial prefrontal cortex, rather than after adult lesions of VH, suggesting that the neonatal VH lesion may affect functional development of the medial prefrontal cortex. These results demonstrate that in rats with neonatally induced excitotoxic VH lesions, behavioral indices consistent with increased mesolimbic DA responsivity to stressful and to pharmacologic stimuli emerge only in early adulthood. Homologous mechanisms may underlie certain aspects of the pathophysiology of schizophrenia.

Tyrosine augments acute clozapine- but not haloperidol-induced dopamine release in the medial prefrontal cortex of the rat: an in vivo microdialysis study.

Tyrosine availability can influence dopamine (DA) synthesis in highly electrophysiologically active DAergic neurons, such as those innervating the medial prefrontal cortex (MPFC). Whether tyrosine concentrations can also affect MPFC extracellular DA concentrations, measured in vivo, is not known. Since clozapine preferentially activates mesocortical DA neurons, we posited that tyrosine administration to a clozapine-pretreated rat would enhance the clozapine-induced augmentation of MPFC extracellular DA concentrations. Tyrosine alone (25-50mg/kg IP) did not affect mesocortical or striatal extracellular DA concentrations measured by in vivo microdialysis. Given 30 minutes after clozapine (10 mg/kg), tyrosine (50 mg/kg) significantly prolonged the clozapine-induced increase in MPFC extracellular DA concentrations but had no effect in the striatum. In contrast, tyrosine (50 mg/kg) significantly prolonged the haloperidol (1 mg/kg) induced increase in striatal extracellular DA concentrations but had no effect in the MPFC. These data constitute the first in vivo evidence that administration of tyrosine can selectively potentiate the clozapine-evoked increase in mesocortical extracellular DA concentrations.

Clozapine and associated diabetes mellitus.

BACKGROUND: Clozapine is an effective therapy for the treatment of refractory psychosis. Clozapine-associated adverse effects include sedation, weight gain, sialorrhea, palpitations, seizures, and hematologic changes such as agranulocytosis. METHOD: We present a four-case series in which clozapine use was associated with either a de novo onset or severe exacerbation of preexisting diabetes mellitus. RESULTS: The change in glycemic control was not significantly related to weight gain. Three of the patients have been able to continue on clozapine therapy and have experienced a reduction in psychotic symptoms. CONCLUSION: Patients with a family history of diabetes mellitus or with preexisting diabetes mellitus may need to have blood sugar monitored closely during initiation of clozapine treatment.

Clozapine-induced urinary incontinence: incidence and treatment with ephedrine.

BACKGROUND: Treatment with the atypical antipsychotic drug clozapine appears to be associated with an increased incidence of urinary incontinence (UI). We posited that the potent anti-alpha-adrenergic effects of clozapine were involved, and hence that an alpha-adrenergic agonist would reduce UI. We tested this hypothesis by using ephedrine, an approved alpha-adrenergic agonist. METHOD: Fifty-seven inpatients with schizophrenia or schizoaffective disorder (DSM-IV) who met the Kane criteria for being treatment refractory were treated with clozapine (75-900 mg/day). Patients who developed UI were then openly treated with ephedrine in increasing doses until UI was attenuated or a dose of 150 mg/day was attained. RESULTS: Seventeen patients developed UI as evidenced by either urine-stained sheets/clothing or direct patient reports. In 2 cases, the UI was sufficiently severe that adult diapers had to be used. Comparison of patients who developed UI and those who did not showed that UI was associated with female gender and with concomitant treatment with typical antipsychotic drugs. One patient was treated with a behavioral program, but the remaining 16 patients were treated with ephedrine. Ephedrine treatment was very effective, with 15/16 patients showing improvement within 24 hours after reaching maximum ephedrine dosage. Twelve of 16 (including the 2 most severe) eventually had a complete remission of their UI. In the remaining 4 patients, 3 had a reduction in the frequency of UI and 1 showed no response. These benefits have been maintained over the course of 12 months of subsequent treatment for several patients. There were no side effects associated with the use of ephedrine nor were there any changes in neuropsychiatric status. CONCLUSION: Ephedrine appears to be a safe and effective treatment clozapine-associated UI. By inference, it is likely that clozapine may cause UI via its anti-alpha-adrenergic properties.

Increased sensitivity to the sensorimotor gating-disruptive effects of apomorphine after lesions of medial prefrontal cortex or ventral hippocampus in adult rats.

Sensorimotor gating of the startle reflex is impaired in humans with schizophrenia and in rats after mesolimbic D2 dopamine receptor activation. The loss of startle gating after D2 activation in rats has been used as an animal model of impaired sensorimotor gating in schizophrenia, because the ability of antipsychotics to restore startle gating in D2-activated rats correlates significantly with antipsychotic clinical potency. Substantial evidence indicates that the pathophysiology of schizophrenia includes structural and functional deficits in prefrontal and temporal regions, particularly the dorsolateral prefrontal cortex and the hippocampus and parahippocampal gyrus. The present study assessed startle gating in adult rats after ibotenic acid lesions of the medial prefrontal cortex or ventral hippocampus. Medial prefrontal cortex lesioned rats exhibited normal startle amplitude and normal sensorimotor gating, as reflected by prepulse inhibition (PPI) of the startle reflex. Hippocampus lesioned rats exhibited elevated startle amplitude, and similar to rats with medial prefrontal cortex lesions, did not show significant changes in basal PPI. Low doses of the mixed dopamine agonist apomorphine did not significantly reduce PPI in sham lesioned rats, but significantly disrupted PPI in both medial prefrontal cortex- and ventral hippo-campus lesioned rats. These data are consistent with the hypothesis that cell damage in frontal and temporal cortex increases the sensitivity to the sensorimotor gating-disruptive effects of dopamine receptor activation.

Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes in prepulse inhibition of startle and its disruption by apomorphine.

Neonatal excitotoxic hippocampal damage in the rat results in postpubertal onset of a variety of abnormal behaviors related to excessive dopaminergic transmission in the mesolimbic/nigrostriatal system, and thus may be considered an animal model of some aspects of schizophrenia. Because sensorimotor gating is impaired in adult patients with schizophrenia and in rats with experimentally induced mesolimbic dopamine hyperactivity, the present experiments investigated the effects of neonatal (postnatal day 7, PD7) ibotenic acid (3 micrograms) lesions of the ventral hippocampus (VH) on the amplitude and prepulse inhibition (PPI) of acoustic startle in prepubertal (PD35) and postpubertal (PD56) rats. Startle was elicited using 105 and 118-dB pulses alone or preceded by 4, 8, or 16 dB above-background prepulses in rats treated with vehicle or apomorphine (APO; 0.025 or 0.1 mg/kg SC). At PD35, PPI in VH-lesioned rats did not differ significantly from these measures in sham operated rats. Apomorphine significantly increased startle amplitude and reduced PPI in both sham operated and VH-lesioned rats at PD35. At PD56, startle amplitude in VH-lesioned rats was not significantly different from controls, but PPI was reduced significantly compared to controls. Ventral hippocampus lesioned rats also exhibited an exaggerated reduction in PPI after treatment with APO. These findings provide further evidence of postpubertal impairments that may be related to increased mesolimbic dopamine transmission and receptor sensitivity in rats with neonatal hippocampal damage, and provide further support for the fidelity of this animal model of schizophrenia.

Effect of clozapine on motor function in schizophrenic patients.

It is well established that clozapine is less likely than typical antipsychotic drugs to cause clinically discernible extrapyramidal side-effects. There is a paucity of data, however, on clozapine's motor effects. In this report we compare normal controls to groups of chronic schizophrenic patients treated with either typical antipsychotic drugs or with clozapine. Motor function was measured with a target-matching task, a test relying on submaximal sustained force control. Results indicated that patients on clozapine performed with significantly lower accuracy (greater variability) of force control. Even though the clozapine patients were treatment resistant to typical antipsychotic drugs, and many had a history of tardive dyskinesia, we postulate that the observed deficit is likely due to clozapine treatment rather than to earlier treatments or other factors. The observed force control deficit may be the result of an increase in myoclonus and a generally lower level of overall motor activity.

Cerebral ventricular enlargement in schizophreniform disorder does not progress. A seven year follow-up study.

Ten patients, who underwent computerized tomography (CT) study during evaluation for first episode schizophreniform psychosis were restudied an average of 7 years later. Of the 10 patients, 7 were found to carry a diagnosis of schizophrenia at follow-up. In this subgroup, there was no significant change in the mean ventricular brain ratio measure of cerebral ventricular size between the index and follow-up scans. These findings are consistent with the hypothesis that ventricular enlargement is present at the onset of schizophrenia and does not progress with duration of illness or treatment.

Clozapine effects on force control in schizophrenic patients.

We previously reported significant differences in force control (FC) function between schizophrenics treated with typical antipsychotic drugs (APD) and those treated with clozapine. Clozapine treatment was associated with an attenuation of the capacity for fine motor control. We now report that a test-retest study with 41 treatment-refractory patients confirms our earlier finding; the FC deficit is due primarily to clozapine treatment. An additional comparison was made with 10 patients who were administered the FC test repeatedly through the initial clozapine titration interval of 6-8 weeks. The results suggest that two distinct clozapine effects can be distinguished, an initial transient stage characterized by 'drowsiness' and a subsequent stage with dose-dependent emerging myoclonic features.

Prefrontal cortical sulcal widening associated with poor treatment response to clozapine.

Increased sulcal widening in the prefrontal cortex of patients with schizophrenia may be associated with a poor treatment response to clozapine. To further evaluate this, we examined data from patients treated with clozapine in our center. Patients with the greatest degree of improvement (n=26) and those with no improvement (n=10) were compared. Computerized tomography (CT) scans were rated blindly on a visual scale of prefrontal sulcal widening. Patients with the greatest degree of functional improvement had significantly less prefrontal sulcal widening than those whose symptoms remained unchanged. There was no relationship between clozapine response and general sulcal widening. These data support the link between the superior therapeutic efficacy of clozapine and the integrity of the prefrontal cortex.

Persistent elevations in dopamine and its metabolites in the nucleus accumbens after mild subchronic stress in rats with ibotenic acid lesions of the medial prefrontal cortex.

This study assessed the possible influence of the medial prefrontal cortex (MPFC) on the response of subcortical dopamine (DA) systems to subchronic, mild stress. DA and its metabolites as well as noradrenaline were assayed in the nucleus accumbens and corpus striatum, 1 and 7 days after one week of daily intraperitoneal saline injections (Stress) or no handling (No stress), in rats with sham (Sham) or ibotenic acid (IA) lesions of the MPFC. One day after the last saline injection the level of dihydroxyphenylacetic acid (DOPAC) was elevated in the nucleus accumbens of IA/Stress rats in comparison to the Sham/No stress, Sham/Stress, and IA/No Stress groups. Levels of mesolimbic DA, DOPAC and homovanillic acid were still elevated 7 days after the last injection in IA/Stress animals in comparison to all other groups. There were no other significant differences between the groups. The data suggest that in rats with MPFC impairment, mild subchronic stress can induce alterations in mesolimbic DA activity that persist beyond the duration of the stress.

Ibotenic acid lesion of the ventral hippocampus differentially affects dopamine and its metabolites in the nucleus accumbens and prefrontal cortex in the rat.

To determine the influence of neurons of the ventral hippocampus on dopamine (DA) turnover in other limbic areas, spontaneous and amphetamine-induced locomotion as well as DA and its metabolites were assayed in nucleus accumbens, medial prefrontal cortex and anteromedial striatum, 14 and 28 days after bilateral ibotenic acid (IA) or sham lesions of the ventral hippocampus in the rat. Spontaneous locomotion was increased 28 days postoperatively, while D-amphetamine induced locomotion was augmented both 14 and 28 days postoperatively in IA lesioned animals. DA levels in the nucleus accumbens were decreased on the 14th, but increased on the 28th day after the lesion. Dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and the DOPAC/DA ratio in the medial prefrontal cortex (MPFC) were reduced 28 days postoperatively. Moreover, there was a significant negative correlation between the DOPAC/DA ratio in the MPFC and DA levels in the nucleus accumbens at this time point. These data indicate that a lesion of the ventral hippocampus can produce differential changes in cortical and limbic DA activity. Implications for an animal model of schizophrenia are considered.

Effect of ibotenic acid lesions of the medial prefrontal cortex on amphetamine-induced locomotion and regional brain catecholamine concentrations in the rat.

To determine the influence of intrinsic medial prefrontal cortex (MPFC) neurons on regional brain catecholamine turnover, dopamine (DA) and its metabolites were assayed in several brain areas 14 and 28 days after bilateral ibotenic acid (IA) lesions of the MPFC in the rat. The locomotor response to D-amphetamine was also assessed. On the 14th postoperative day levels of DA, homovanillic acid concentrations and 3,4-dihydroxyphenylacetic acid were elevated in the anterior striatum of IA-lesioned animals. Spontaneous and amphetamine-induced locomotion were also increased. These changes disappeared by the 28th postoperative day. It is concluded that destruction of the efferents of the MPFC induces transient increases in DA turnover within the medial striatum and transiently increases spontaneous and amphetamine-induced locomotion.

Evidence for a frontocortical-septal glutamatergic pathway and compensatory changes in septal glutamate uptake after cortical and fornix lesions in the rat.

To determine the source of glutamatergic input to the septum and to the nucleus accumbens septi, glutamate uptake was assessed after transections of the frontal cortex and/or fornix. Uptake in the septum and accumbens was reduced by 25 and 30% respectively, 6 days after bilateral frontal cortex transections. Both indices returned to control levels 30 days postoperatively. In contrast, while unilateral fornix transection did not affect uptake in the accumbens at either day 6 or 30, uptake in the septum was significantly reduced (25-35%) at both times. When a unilateral transection of the fornix was performed in rats with a pre-existing bilateral ablation of the frontal cortex, a further reduction in uptake was observed in the septum (50-60% at both 6 and 30 days after the fornix transection). The data implicate glutamate as a neurotransmitter in frontocortico-septal projections and suggest that the contribution of the hippocampo-septal system to total glutamate uptake in the septum is increased following ablation of the frontocortico-septal system.

Serotonin 5-HT3 receptors in schizophrenia: a postmortem study of the amygdala.

Alterations in density of some serotonin receptor sites (5-HT1A receptors, 5-HT2 receptors and 5-HT uptake sites) have been reported in postmortem studies of brain obtained from subjects with schizophrenia, suggesting a disturbance in serotonergic transmission in schizophrenia. The purpose of the present study is to investigate [3H]-LY278584 binding to serotonin 5-HT3 receptors in postmortem samples of amygdala from schizophrenic and matched control subjects. As all of the schizophrenic patients but none of the controls had been treated with neuroleptics, we first investigated in rodents the effects of short-term and long-term haloperidol administration on limbic 5-HT3 receptors, and we found no effects. No differences in the maximum number of 5-HT3 binding sites (Bmax) or equilibrium dissociation constant (Kd) between schizophrenics and controls were found in amygdala. This study does not support the presence of an alteration of 5-HT3 receptors in amygdala in schizophrenic patients.

D1 and D2 receptor modulation in rat striatum and nucleus accumbens after subchronic and chronic haloperidol treatment.

The antipsychotic effects of neuroleptic drugs are believed to be achieved by chronic blockade of dopaminergic transmission in the limbic system. Nevertheless, the effects of chronic (3-12 months) haloperidol administration on the dopaminergic transmission in the nucleus accumbens of rodents remains poorly understood. Studies of spontaneous locomotor activity (SLA), a behavioral measure related to limbic dopamine transmission, and of dopamine D2 receptor density in the nucleus accumbens after chronic oral haloperidol treatment have yielded conflicting results. We evaluated these indices after 8 months of parenteral administration of haloperidol decanoate. We report here that, after 8 months of parenteral treatment, SLA stays significantly decreased and D2 receptors in the nucleus accumbens exhibit the same up-regulation as in the striatum (about 50%). These results fail to support the notion of a different pattern of D2 receptor adaptation to neuroleptic treatment between the nucleus accumbens and the striatum. In contrast, dopamine D1 receptors were found to be unaffected in the nucleus accumbens but decreased in the striatum by 22% after 8 months of treatment. This observation could be relevant to the pathogenesis of tardive dyskinesia.

The neuropathology of schizophrenia.

Insofar as schizophrenia is a neuropsychiatric syndrome involving the brain, neuropathology is a promising, if not essential investigative approach. Although traditional neuropathology has yet to yield a pathognomonic lesion in schizophrenia, there have been no shortages of findings. Unfortunately, many of these findings have not only failed to be pathognomonic, but they have not been consistently replicated. Fortunately, newer neuropathological techniques, such as post-mortem neurochemistry, have resulted in findings among the most reproducible in schizophrenia research. Although one of these, increased dopamine receptors in the basal ganglia of schizophrenic patients, has been replicated many times, it suffers from doubts as to its clinical relevance. Are these increases in dopamine receptors primary to the illness or a side effect of the treatment? This article discusses the relevance of this finding, reviews other highlights of post-mortem neurochemistry and traditional neuropathology, and discusses new horizons such as autoradiography, immunocytochemistry, and neuronal morphometrics.

Exposure of a 'witness rat' to one treated with beta-carboline FG 7142 does not increase dopamine turnover in the medial prefrontal cortex of the 'witness rat'.

A method for selectively activating the dopaminergic field of the prefrontal cortex would be highly useful for studies of mesocortical dopamine systems. When a rat ('witness' rat) is exposed to a rat that is undergoing footshock, prefrontocortical dopamine metabolism is selectively increased in the witness rat. Since the anxiogenic beta-carboline FG 7142 mimics many of the effects of footshock, we hypothesized that exposure of a witness-rat to a rat treated with FG 7142 would also increase dopamine metabolism in the prefrontal cortex. We found that while as expected, FG 7142 itself increased prefrontal cortex dopamine metabolism, there was no significant change in dopamine metabolism in the witness rat. Thus exposure to a rat treated with FG 7142 does not selectively activate the mesocortical dopamine system.