Clozapine-Induced ERK1 and ERK2 Signaling in Prefrontal Cortex Is Mediated by the EGF Receptor

The atypical antipsychotic drug clozapine is effective in treatment-refractory schizophrenia. The intracellular signaling pathways that mediate clozapine action remain unknown. A potential candidate is the mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK-ERK) cascade that links G-protein-coupled receptor and ErbB growth factor signaling systems, thereby regulating synaptic plasticity and connectivity, processes impaired in schizophrenia. Here, we examined how clozapine differentially modulated phosphorylation of the MAPK isoforms, ERK1/ERK2 in primary murine prefrontal cortical neurons compared to the typical antipsychotic drug haloperidol. While clozapine and haloperidol acutely decreased cortical pERK1 activation, only clozapine but not haloperidol stimulated pERK1 and pERK2 with continued drug exposure. This delayed ERK increase however, did not occur via the canonical dopamine D₂-Gi/o-PKA or serotonin 5HT_2A-Gq-phospholipase-C-linked signaling pathways. Rather, epidermal growth factor (EGF) receptor signaling mediated clozapine-induced ERK activation, given dose-dependent reduction of pERK1 and pERK2 stimulation with the EGF receptor inhibitor, AG1478. Immunocytochemical studies indicated that clozapine treatment increased EGF receptor (Tyr1068) phosphorylation. In vivo mouse treatment studies supported the in vitro findings with initial blockade, subsequent activation, and normalization of the cortical ERK response over 24 h. Furthermore, in vivo clozapine-induced ERK activation was significantly reduced by AG1478. This is the first report that clozapine action on prefrontal cortical neurons involves the EGF signaling system. Since EGF receptor signaling has not been previously linked to antipsychotic drug action, our findings may implicate the EGF system as a molecular substrate in treatment-resistant schizophrenia.     

Differential effects of antipsychotics on hippocampal presynaptic protein expressions and recognition memory in a schizophrenia model in mice

We compared the effects of subchronic clozapine and haloperidol administration on the expression of SNAP-25 and synaptophysin in an animal model of schizophrenia based on the glutamatergic hypothesis. Mice were first treated with a non-competitive NMDA antagonist MK-801 (0.3 mg/kg/day) or saline for 5 days, and then clozapine (5 mg/kg/day), haloperidol (1 mg/kg/day) or saline was administered for two weeks. The locomotion test, as a behavioral model of the positive symptoms of schizophrenia, was applied after MK-801/saline administration on day 6 for acute effects and after antipsychotic/saline administration on day 19 for enduring effects on mice activity. Memory function was assessed by the Novel Object Recognition (NOR) test, one day after the last day of antipsychotic/saline administration (day 20). Western Blotting technique was used to determine SNAP-25 and synaptophysin expressions in the hippocampus and frontal cortex. Both antipsychotics reversed the enhanced locomotion effects of MK-801. MK-801 and haloperidol decreased recognition memory performance. On the other hand, clozapine did not compromise memory. It also did not reverse the negative effects of MK-801 on memory performance. MK-801 did not change SNAP-25 and synaptophysin expressions in the hippocampus and frontal cortex. Clozapine increased hippocampal SNAP-25, decreased hippocampal synaptophysin expression, whereas frontal SNAP-25 and synaptophysin expressions remained unchanged. Haloperidol had no effects on levels of SNAP-25 and synaptophysin in the frontal cortex and hippocampus. These findings support the idea that the differential effects of clozapine might be related to its plastic effects and synaptic reorganization of the hippocampus.     

Effects of clozapine and olanzapine on cortical thickness in childhood-onset schizophrenia

BackgroundLittle is known about the effects of antipsychotic medications on gray matter (GM) in schizophrenia. Although clozapine remains the most effective antipsychotic medication in treatment-refractory cases, it is unknown whether it has a differential effect on GM development.MethodsIn an exploratory analysis, we used automated cortical thickness measurements and prospectively scanned childhood-onset schizophrenia (COS) patients who were maintained on one medication. Two atypical antipsychotic medications, clozapine (n = 12, 37 scans) and olanzapine (n = 12, 33 scans) were compared with respect to effects on cortical development, in contrast to GM trajectories of matched controls.ResultsThere were no significant differences in the trajectories of cortical thickness between the two treatment groups with the exception of a small circumscribed area in the right prefrontal cortex, where the olanzapine group showed thicker cortex. As expected, both groups showed thinner GM compared to matched controls.ConclusionsAlthough these analyses do not rule out effects of antipsychotic medications on GM development in schizophrenia, they show no differential effect between clozapine and olanzapine on GM trajectory.     

Differential effects of clozapine and haloperidol on ketamine-induced brain metabolic activation

Subanesthetic doses of N-methyl- -aspartate (NMDA) receptor antagonists such as ketamine and phencyclidine precipitate psychotic symptoms in schizophrenic patients. In addition, these drugs induce a constellation of behavioral effects in healthy individuals that resemble positive, negative, and cognitive symptoms of schizophrenia. Such findings have led to the hypothesis that decreases in function mediated by NMDA receptors may be a predisposing, or even causative, factor in schizophrenia. The present study examined the effects of the representative atypical (clozapine) and typical (haloperidol) antipsychotic drugs on ketamine- induced increases in -2-deoxyglucose (2-DG) uptake in the rat brain. As previously demonstrated, administration of subanesthetic doses of ketamine increased 2-DG uptake in specific brain regions, including medial prefrontal cortex, retrosplenial cortex, hippocampus, nucleus accumbens, basolateral amygdala, and anterior ventral thalamic nucleus. Pretreatment of rats with 5 or 10 mg/kg clozapine alone produced minimal or no change in 2-DG uptake, yet clozapine completely blocked ketamine-induced changes in 2-DG uptake in all brain regions studied. In striking contrast, a dose of haloperidol (0.5 mg/kg) that produces a substantial cataleptic response, potentiated, rather than blocked, ketamine-induced activation of 2-DG uptake. These results demonstrate, in a model with potential relevance to schizophrenia, a striking neurobiological difference between the actions of prototypical typical and atypical antipsychotic drugs. The dramatic blockade by clozapine of ketamine-induced brain metabolic activation suggests that antagonism of the consequences of reduced NMDA receptor function could contribute to the superior therapeutic effects of this atypical antipsychotic agent. The results also suggest that this model of ketamine-induced alterations in 2-DG uptake may be extremely useful for understanding the complex neural mechanisms of atypical antipsychotic drug action.     

Reduced basal and phencyclidine-induced expression of heat shock protein-70 in rat prefrontal cortex by the atypical antipsychotic abaperidone

The effect of antipsychotic treatment on basal and phencyclidine (PCP)-induced heat shock protein-70 (hsp70) mRNA expression was studied in the rat striatum and in the prefrontal cortex. Abaperidone, a novel drug with an atypical antipsychotic profile, was compared, at pharmacologically equivalent doses, with the atypical antipsychotics clozapine and risperidone and also with haloperidol, a classical antipsychotic. Abaperidone and clozapine reduced basal hsp70 mRNA expression in the rat striatum and in the prefrontal cortex. No change in either region was found after haloperidol, whereas risperidone reduced hsp70 mRNA in the striatum but not in the prefrontal cortex. The N-methyl-D-aspartate (NMDA) receptor antagonist PCP significantly elevated hsp70 mRNA levels in the prefrontal cortex, an elevation that was potentiated by haloperidol and prevented by all of the atypical antipsychotics tested. Since hsp70 has been associated to some schizophrenia symptoms, we suggest that reduced hsp70 in the prefrontal cortex, a cortical area that plays a critical role in the etiology of many schizophrenia symptoms, may be linked to an atypical profile of antipsychotics, such as clozapine, and possibly also abaperidone.     

Efficacy and tolerability of quetiapine in poorly responsive, chronic schizophrenia

With the notable exception of clozapine, there is at present insufficient information on the efficacy of atypical antipsychotic medications in patients with poorly responsive schizophrenia. The present study reports on the efficacy and tolerability of quetiapine and haloperidol in patients with schizophrenia who showed no response to treatment with fluphenazine. This study is a post hoc subanalysis of an 8-week, double-blind study of patients receiving quetiapine 600 mg/day or haloperidol 20 mg/day. The proportion of patients classified as "Clinical Global Impression responders" (defined as Clinical Global Impression Severity of Illness score of < or = 3 at study end) was greater in the quetiapine group compared with the haloperidol group (51% vs. 25%; P = 0.023). Overall, quetiapine was well tolerated with less extrapyramidal side-effects and reduction in prolactin when compared to haloperidol. Weight gain was modest but more apparent in quetiapine-treated patients. Quetiapine is an appropriate treatment choice in patients who do not respond to prior antipsychotic treatment.     

Interleukin-1 beta gene polymorphism and its interactions with neuregulin-1 gene polymorphism are associated with schizophrenia

Interleukin-1β (IL-1β) and neuregulin-1 (NRG-1) have an important role in development of the central nervous system. Several recent studies suggest that their genetic polymorphisms are associated with schizophrenia. We studied the effects of the IL-1β gene (IL-1B) -511 and NRG-1 SNP8NRG221533 polymorphisms and their interactions on the risk and age of onset of schizophrenia in 113 Finnish schizophrenic patients and 393 healthy controls. The allele and genotype frequencies of IL-1B and NRG-1 did not differ between schizophrenic patients and healthy controls, but the risk of schizophrenia was more than 10 times higher (odds ratio 10.20, 95% CI 2.53–41.09, p = 0.001) among subjects with the IL-1B 2.2, NRG-1 CC genotypes compared to subjects with the IL-1B 2.2, NRG-1 T-allele carriage. There was also a trend for an association between the interaction between IL-1B and NRG-1 polymorphisms and the age at onset of schizophrenia (χ² = 2.80; df = 1; p = 0.09, log rank test). IL-1B-511 allele 1 homozygotes had a significantly higher age of onset than allele 2 carriers (mean age of onset 25.9 ± 7.7 and 22.7 ± 5.4 years, t-test: t = 2.46; p = 0.032). Our results suggest that there is an interaction between the IL-1B and NRG-1 genes in schizophrenia. In addition, the IL-1B-511 polymorphism seems to be associated with the age at onset of schizophrenia.     

Expression of exocytosis proteins in rat supraoptic nucleus neurones

In magnocellular neurones of the supraoptic nucleus (SON), the neuropeptides vasopressin and oxytocin are synthesised and packaged into large dense-cored vesicles (LDCVs). These vesicles undergo regulated exocytosis from nerve terminals in the posterior pituitary gland and from somata/dendrites in the SON. Regulated exocytosis of LDCVs is considered to involve the soluble N-ethylmaleimide sensitive fusion protein attachment protein receptor (SNARE) complex [comprising vesicle associated membrane protein 2 (VAMP-2), syntaxin-1 and soluble N-ethylmaleimide attachment protein-25 (SNAP-25)] and regulatory proteins [such as synaptotagmin-1, munc-18 and Ca(2+) -dependent activator protein for secretion (CAPS-1)]. Using fluorescent immunocytochemistry and confocal microscopy, in both oxytocin and vasopressin neurones, we observed VAMP-2, SNAP-25 and syntaxin-1-immunoreactivity in axon terminals. The somata and dendrites contained syntaxin-1 and other regulatory exocytosis proteins, including munc-18 and CAPS-1. However, the distribution of VAMP-2 and synaptotagmin-1 in the SON was limited to putative pre-synaptic contacts because they co-localised with synaptophysin (synaptic vesicle marker) and had no co-localisation with either oxytocin or vasopressin. SNAP-25 immunoreactivity in the SON was limited to glial cell processes and was not detected in oxytocin or vasopressin somata/dendrites. The present results indicate differences in the expression and localisation of exocytosis proteins between the axon terminals and somata/dendritic compartment. The absence of VAMP-2 and SNAP-25 immunoreactivity from the somata/dendrites suggests that there might be different SNARE protein isoforms expressed in these compartments. Alternatively, exocytosis of LDCVs from somata/dendrites may use a different mechanism from that described by the SNARE complex theory.     

Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs

Typical and atypical antipsychotic drugs, though both effective, act on different neurotransmitter receptors and are dissimilar in some clinical effects and side effects. The typical antipsychotic drug haloperidol has been shown to cause a decrease in the expression of brain-derived neurotrophic factor (BDNF), which plays an important role in neuronal cell survival, differentiation, and neuronal connectivity. However, it is still unknown whether atypical antipsychotic drugs similarly regulate BDNF expression. We examined the effects of chronic (28 days) administration of typical and atypical antipsychotic drugs on BDNF mRNA expression in the rat hippocampus using in situ hybridization. Quantitative analysis revealed that the typical antipsychotic drug haloperidol (1 mg/kg) down-regulated BDNF mRNA expression in both CA1 (P < 0.05) and dentate gyrus (P < 0.01) regions compared with vehicle control. In contrast, the atypical antipsychotic agents clozapine (10 mg/kg) and olanzapine (2.7 mg/kg) up-regulated BDNF mRNA expression in CA1, CA3, and dentate gyrus regions of the rat hippocampus compared with their respective controls (P < 0.01). These findings demonstrate that the typical and atypical antipsychotic drugs differentially regulate BDNF mRNA expression in rat hippocampus.     

Effects of atypical antipsychotics on the syndromal profile in treatment-resistant schizophrenia

BACKGROUND: There has been considerable support for the observation that atypical antipsychotics have a broader range of therapeutic effects than traditional antipsychotics. We are exploring whether this expanded clinical efficacy can also be seen in patients with treatment-resistant schizophrenia. METHOD: The subjects were 157 treatment-resistant inpatients diagnosed with DSM-IV schizophrenia or schizoaffective disorder. They were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol in a 14-week double-blind trial and rated with a standard measure of clinical antipsychotic efficacy (Positive and Negative Syndrome Scale [PANSS]). Factor analysis at baseline and endpoint together with changes in 5 PANSS-derived factors were examined. Data were gathered from June 1996 to December 1999. RESULTS: The underlying PANSS factor structure, as indicated by the factor loadings, was essentially identical at baseline and endpoint. At baseline, the excitement factor was followed by the positive, negative, cognitive, and depression/anxiety factors, explaining 49.4% of the total variance. At endpoint, the positive factor was followed by the negative, excitement, cognitive, and depression/anxiety factors, explaining 55.5% of the total variance. The endpoint data indicated statistically significant (p <.05) improvements over time on the positive factor for all 3 atypicals, but not for haloperidol. The negative factor showed significant improvement for clozapine and olanzapine, with significant worsening for haloperidol. Clozapine, olanzapine, and risperidone were superior to haloperidol on the negative factor, while clozapine was also superior to risperidone. The cognitive factor showed significant improvement for all atypicals, as did the depression/anxiety factor. Only clozapine showed improvement on the excitement factor and was superior to both haloperidol and risperidone. CONCLUSIONS: Treatment with atypical antipsychotics did not substantially change the underlying PANSS 5-factor structure. However, antipsychotic treatment with all 3 atypical medications was associated with significant improvements on 3 of 5 syndromal domains (positive, cognitive, and depression/anxiety) of schizophrenia. Clozapine and olanzapine also showed improvement on the negative factor. Only clozapine was associated with improvement on the excitement domain. This finding confirms that atypicals are associated with improvement of an expanded spectrum of symptoms in treatment-resistant patients.     

Risperidone-induced increase of plasma norepinephrine is not correlated with symptom improvement in chronic schizophrenia.

BACKGROUND: Previous studies have shown an increase in plasma levels of norepinephrine (NE) after clozapine treatment of schizophrenia. This effect has been suggested to relate to improvement in symptoms. METHODS: To test whether other novel antipsychotic drugs have such an effect, the present experiment examined schizophrenic symptoms and plasma levels of NE before and after 5 weeks of treatment with risperidone or haloperidol. RESULTS: Risperidone, but not haloperidol, significantly increased plasma NE; however, there was no correlation of this effect with clinical improvement on any symptom scale. CONCLUSIONS: This finding suggests that risperidone shares similar properties with clozapine in enhancing peripheral NE, but that these changes in plasma NE may not be a consistent indicator of atypical antipsychotic drug efficacy.     

A case of recurrent neuroleptic malignant syndrome

Summary:Neuroleptic malignant syndrome (NMS) is a life-threatening neurologic complication associated with the use of neuroleptic agents and characterized by a distinctive clinical syndrome of fever, r...     

Neuregulin-1 genotypes and eye movements in schizophrenia

Neuregulin-1 (NRG-1) is a putative susceptibility gene for schizophrenia but the neurocognitive processes that may involve NRG-1 in schizophrenia are unknown. Deficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes, which may be associated with brain dysfunctions underlying the pathophysiology of schizophrenia. The aim of this study was to investigate the associations of NRG-1 genotypes with AS and SPEM in schizophrenia patients and healthy controls. Patients (N = 113) and controls (N = 106) were genotyped for two NRG-1 single nucleotide polymorphisms (SNPs); SNP8NRG222662, a surrogate marker for the originally described Icelandic NRG-1 risk haplotype, and SNP8NRG243177, which has recently been associated with individual differences in brain function. Subjects underwent infrared oculographic assessment of AS and SPEM. The study replicates previous findings of impaired AS and SPEM performance in schizophrenia patients (all P < 0.005; all d = 0.5–1.5). SNP8NRG243177 risk allele carriers had marginally increased variability of AS spatial error (P = 0.050, d = 0.3), but there were no significant genotype effects on other eye movement variables and no significant diagnosis-by-genotype interactions. Generally, risk allele carriers (G allele for SNP8NRG222662 and T allele for SNP8NRG243177) had numerically worse performance than non-carriers on most AS and SPEM variables. The results do not suggest that NRG-1 genotype significantly affects AS and SPEM task performance. However, the power of the sample to identify small effects is limited and the possibility of a type II error must be kept in mind. Larger samples may be needed to reliably investigate such gene effects on oculomotor endophenotypes.     

Associations of Clozapine Use With Psychosocial Functioning and Quality of Life in Patients With Schizophrenia: A Community-Based Cross-Sectional Study

ObjectiveMore attempts have been made recently to improve psychosocial functioning and quality of life in patients with schizophrenia, due to their crucial role in long-term outcomes. Previous studies on the effects of clozapine on psychosocial functioning have been limited in terms of generalizability and application to clinical practice. This study examined the relationship of clozapine use with psychosocial functioning and quality of life in patients with schizophrenia in a real-world setting. MethodsData were obtained from a survey targeting community-dwelling patients with schizophrenia. The Behavior and Symptom Identification Scale (BASIS) and Satisfaction with Life Scale (SWLS) were administered to evaluate psychosocial functioning and quality of life, and patients were classified into Clozapine and Non-clozapine groups. Group differences were assessed using ANCOVA, with additional sensitivity analyses for participants on atypical antipsychotic medications only. ResultsOf 292 patients, the Clozapine group (n=34) had significantly better psychosocial functioning and quality of life than the Nonclozapine group (n=258), as demonstrated by their low BASIS score (F=4.651, df=1, 290, p=0.032) and high SWLS score (F=14.637, df=1, 290, p<0.001). Similar findings for psychosocial outcomes were observed in the analyses of the atypical antipsychotic subgroup (n=195). ConclusionFor optimal recovery in schizophrenia, restoration of impaired social functioning and enhanced satisfaction with life are essential. In this study, clozapine use was related to high levels of psychosocial functioning and quality of life in real-world settings. Further research on the causal relationship between clozapine use and psychosocial functioning is needed.     

Measurement and comparison of serum neuregulin 1 immunoreactivity in control subjects and patients with schizophrenia: an influence of its genetic polymorphism

Neuregulin-1 (NRG1) gene is implicated in the etiology or neuropathology of schizophrenia, although its biological contribution to this illness is not fully understood. We have established an enzyme-linked immunosorbent assay (ELISA), which recognizes the NRG1β1 immunoglobulin-like (Ig) domain, and measured soluble Ig-NRG1 immunoreactivity in the sera of chronic schizophrenia patients (n = 40) and healthy volunteers (n = 59). ELISA detected remarkably high concentrations of Ig-NRG1 immunoreactivity in human serum (mean 5.97 ± 0.40 ng/mL, ~213 ± 14 pM). Gender and diagnosis exhibited significant effects on serum Ig-NRG1 immunoreactivity. Mean Ig-NRG1 immunoreactivity in the schizophrenia group was 63.2% of that measured in the control group. Ig-NRG1 immunoreactivity in women was 147.1% of that seen in men. We also attempted to correlate six SNPs of NRG1 genome with serum Ig-NRG1 immunoreactivity. Analysis of covariance with compensation for gender identified a significant interaction between diagnosis and SNP8NRG243177 allele. The T allele of this SNP significantly contributed to the disease-associated decrease in Ig-NRG1 immunoreactivity. Although we hypothesized a chronic influence of antipsychotic medications, there was no significant effect of chronic haloperidol treatment on serum Ig-NRG1 immunoreactivity in monkeys. These findings suggest that serum NRG1 levels are decreased in patients with chronic schizophrenia and influenced by their SNP8NRG243177 alleles.     

Dopamine and serotonin metabolism in response to chronic administration of fluvoxamine and haloperidol combined treatment

Summary Treating primary ‘negative symptoms’ of schizophrenia with a combination of a typical antipsychotic and a selective serotonin reuptake inhibitor, is more effective than with antipsychotic alone and is similar to the effect of the atypical antipsychotic, clozapine. The mechanism of this treatment combination is unknown and may involve changes in dopaminergic and serotonin systems. We studied dopamine and serotonin metabolism in different rat brain areas at 1.5 and 24 h after the last dosage of chronic treatment (30 days), with haloperidol plus fluvoxamine, each drug alone, and clozapine. Haloperidol-fluvoxamine combination, haloperidol, and clozapine treatments increased striatal and frontal cortex dopamine turnover and reduced striatal tyrosine hydroxylase activity at 1.5 h. At 24 h both dopamine turnover and tyrosine hydroxylase activity were reduced. Thus, in chronically treated animals, release of striatal dopamine increases following a drug pulse and returns to baseline by 24 h. Serotonin and 5-hydroxyindoleacetic acid concentrations were decreased at 1.5 h in haloperidol-fluvoxamine and clozapine groups and returned to normal levels by 24 h. A limited behavioral assessment showed that treatment with haloperidol plus fluvoxamine reduced motor activity compared to haloperidol, and increased sniffing compared to haloperidol, fluvoxamine and clozapine. These findings indicate that combining antipsychotic with SSRI results in specific changes in dopaminergic and serotonergic systems and in behavior. The possibility that these may be relevant to the mechanism underlying the clinical effectiveness of augmentation treatment warrant further study. An erratum to this article is available at .     

Acute sublethal global hypoxia induces transient increase of GAP-43 immunoreactivity in the striatum of neonatal rats

We assessed immunoreactivity (IR) in the cerebral cortex (CC), hippocampus (Hipp), and striatum (ST) of a growth-associated protein, GAP-43, and of proteins of the synaptic vesicle fusion complex: VAMP-2, Syntaxin-1, and SNAP-25 (SNARE proteins) throughout postnatal development of rats after submitting the animals to acute global postnatal hypoxia (6.5% O(2), 70 min) at postnatal day 4 (PND4). In the CC only the IR of the SNARE protein SNAP-25 increased significantly with age. The hypoxic animals showed the same pattern of IR for SNAP-25, although with lower levels at PND11, and also a significant increase of VAMP-2. SNAP-25 (control): PND11 P < 0.001 vs. PND18, 25, and 40, SNAP-25 (hypoxic): P < 0.001 vs. PND18, 25, and 40; VAMP-2 (hypoxic): P < 0.05 PND11 vs. PND18, and P < 0.01 vs. PND25 and PND40; one-way ANOVA and Bonferroni post-test. In the Hipp, SNAP-25 and syntaxin-1 increased significantly with age, reaching a plateau at PND25 through PND40 in control animals (one-way ANOVA: syntaxin-1: P = 0.043; Bonferroni: NS; SNAP-25: P = 0.013; Bonferroni: P < 0.01 PND11 vs. PND40). Hypoxic rats showed higher levels of significance in the one-way ANOVA than controls (syntaxin-1: P = 0.009; Bonferroni: P < 0.05 PND11 vs. PND25 and P < 0.001 PND11 vs. PND40). In the ST, GAP-43 differed significantly among hypoxic and control animals and the two-way ANOVA revealed significant differences with age (F = 3.23; P = 0.037) and treatment (F = 4.84; P = 0.036). VAMP-2 expression also reached statistical significance when comparing control and treated animals (F = 6.25, P = 0.018) without changes regarding to age. Elevated plus maze test performed at PND40 indicated a lower level of anxiety in the hypoxic animals. At adulthood (12 weeks) learning, memory and locomotor abilities were identical in both groups of animals. With these results, we demonstrate that proteins of the presynaptic structures of the ST are sensitive to acute disruption of homeostatic conditions, such as a temporary decrease of the O(2) concentration. Modifications in the activity of these proteins could contribute to the long term altered responses to stress due to acute hypoxic insult in the neonatal period.     

Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia

Objective

Treatment resistance is a challenge for the management of schizophrenia. It is not always clear whether inadequate response is secondary to medication ineffectiveness, as opposed to medication underexposure due to non‐adherence or pharmacokinetic factors. We investigated the prevalence of subtherapeutic antipsychotic plasma levels in patients identified as treatment‐resistant by their treating clinician.

Method

Between January 2012 and April 2017, antipsychotic plasma levels were measured in 99 individuals provisionally diagnosed with treatment‐resistant schizophrenia by their treating clinicians, but not prescribed clozapine. Patients were followed up to determine whether they were subsequently admitted to hospital.

Results

Thirty‐five per cent of plasma levels were subtherapeutic, and of these, 34% were undetectable. Black ethnicity (P = 0.006) and lower dose (P < 0.001) were significantly associated with subtherapeutic/undetectable plasma levels. Individuals with subtherapeutic/undetectable levels were significantly more likely to be admitted to hospital (P = 0.02).

Conclusion

A significant proportion of patients considered treatment‐resistant have subtherapeutic antipsychotic plasma levels, and this is associated with subsequent admission. The presence of subtherapeutic plasma levels may suggest a need to address adherence or pharmacokinetic factors as opposed to commencing clozapine treatment. While antipsychotic levels are not recommended for the routine adjustment of dosing, they may assist with the assessment of potential treatment resistance in schizophrenia.