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.

Improved method for the measurement of large neutral amino acids in biological matrices.

A high-performance liquid chromatographic method for measuring neutral amino acids in rat sera, brain tissues, and perfusates was developed by using o-phthalaldehyde sulfite as a pre-column derivatization reagent. With the present method, it was possible to separate the neutral amino acids within a single run in 25 min, while the acidic amino acids were eluted near or at the solvent front. The recovery was above 88.8% with a relative standard deviation (RSD) below 4.2%. The within- and between-day assay reproducibility for the determination of rat serum amino acids showed RSDs below 1.35 and 7.61%, respectively. In the present study, the neutral amino acids were assayed with high sensitivity, accuracy and good reproducibility in a relatively short time and on a small sample size.

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.

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.

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.

Differential effects of haloperidol and clozapine on ionotropic glutamate receptors in rats.

Despite multiple lines of investigation the effect of neuroleptics on glutamate-mediated neurotransmission remains controversial. To study the effects of typical and atypical neuroleptics on selected parameters of glutamate-mediated neurotransmission, male Sprague-Dawley rats were randomly assigned to a 21-day oral treatment course with vehicle, haloperidol (HDL), or clozapine (CLZ). Coronal slices of rat brain were then incubated with tritiated ligands to measure NMDA, AMPA, and kainate receptor, and glutamate reuptake site density. Regions of interest included the frontal cortex, anterior cingulate cortex, dorsal striatum, ventral striatum, and the nucleus accumbens. CLZ increased the density of AMPA receptors significantly in the frontal and anterior cingulate cortices compared with normal controls. In the dorsal and ventral striatum, and nucleus accumbens as a whole, CLZ-treated rats had a higher AMPA receptor density compared with both the HDL- and vehicle-treated controls. Additionally, within the nucleus accumbens, CLZ-treated rats had a higher density of AMPA receptors compared with the HDL group in the core, and at trend level in the shell. There was a group by region interaction for NMDA receptor density, primarily reflecting the tendency of HDL treated rats to have high receptor densities in the frontal and anterior cingulate cortices. Kainate receptors and glutamate reuptake site densities did not differ significantly across groups. These results suggest a critical role for glutamate in the mediation of atypical antipsychotic drug action in anatomically-specific regions, and further encourage the investigation of glutamate neurotransmitter systems in schizophrenia.

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.

Sertraline and psychotic symptoms: a case series.

Sertraline and other SSRIs have a relatively favorable side-effect profile and are widely prescribed. We report the emergence of psychotic symptoms during treatment with sertraline in four patients. Three of these patients had a history of psychotic illness and were on antipsychotic medication, when sertraline was added. The psychotic symptoms emerged within 3 days-7 weeks of starting sertraline and resolved on its discontinuation. We wish to alert clinicians to the possibility that sertraline may provoke or exacerbate positive psychotic symptoms, particularly in patients on neuroleptics, with a previous history of psychosis.

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.

Clozapine reduces water-drinking behavior in schizophrenic patients with polydipsia.

Disordered water balance, or polydipsia, is an underassessed and underreported phenomenon present in the severely psychiatrically disabled population. Prevalence rates for polydipsia range from 6.2 to 20%. We followed up five male patients (mean age 43) with chronic schizophrenia who met the Kane criteria for being treatment nonresponders and who, in addition, had marked polydipsia. Three patients had previously received medical care for hyponatremia and had to be placed on fluid restriction when admitted to the hospital. All patients exhibited polydipsia despite high doses of typical antipsychotic drugs. Each patient was treated openly with clozapine (range 450-800 mg/day) for at least 6 months. In each case, there was a decline in the Brief Psychiatric Rating Scale score (preclozapine mean, 63; postclozapine mean, 46), and a marked reduction in fluid-seeking behavior. All fluid restrictions could be lifted, and the patients were discharged from the hospital. During a mean follow-up period of 17 months, during which patients were evaluated weekly, polydipsic behavior that required intervention had not been noted. We conclude that clozapine may be a highly effective treatment for polydipsia in patients with treatment-refractory schizophrenia. Future studies may aim to delineate neurobiologic mechanisms.

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.

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.

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.

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.

The effects of combined prefrontal cortical and hippocampal damage on dopamine-related behaviors in rats.

The effects of excitotoxic damage to both the medial prefrontal cortex (MPFC) and the ventral hippocampus (VH) on behaviors related to mesolimbic/nigrostriatal dopamine (DA) transmission were investigated in the rat. Locomotor activity in a novel environment, after injection of saline, and after d-amphetamine was assessed 2 and 4 weeks after ibotenic acid lesion of both MPFC and VH in adult rats. In addition, stereotypic behaviors and locomotion after apomorphine were evaluated 8 weeks after the lesion. Locomotor activity was significantly enhanced in all testing conditions in lesioned rats as compared with sham-operated animals, while oral stereotypic behaviors elicited by apomorphine were attenuated possibly because they were eclipsed by excessive locomotion. These data indicate that coexisting lesions of the MPFC and VH in adult rats produce potent and long-lasting effects on behaviors believed to be dependent primarily on the mesolimbic DA system. The profile of changes resembles more closely that observed after excitotoxic lesions of the VH alone rather than that after separate MPFC lesion.

Effects of ibotenic acid lesion of the medial prefrontal cortex on dopamine agonist-related behaviors in the rat.

Behavioral responses to apomorphine and to the selective D1 and D2 dopamine receptor agonists SK&F38393 and quinpirole were evaluated in rats following ibotenic acid (IA) or sham lesion of the medial prefrontal cortex (MPFC). IA-lesioned rats showed an increased responsiveness to the postsynaptic effects of all of the dopamine agonists. Patterns of the responses to the selective agonists administered alone and in combination suggest that these effects might be due to selective increases in the sensitivity of postsynaptic D1 receptor-associated mechanisms. In addition, IA-lesioned rats pretreated with saline were hyperactive in comparison to sham-lesioned rats when animals were exposed to a novel open field, but spontaneous motor activity did not differ between these two groups when animals were pretreated with low doses (0.03 mg/kg) of quinpirole. The fact that hyperreactivity observed in lesioned animals is inhibited by a dose of quinpirole that is felt to act presynaptically, selectively attenuating endogenous dopaminergic tone, suggests that effects of the MPFC lesion may be mediated presynaptically as well.

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.