Serdar M. Dursun

Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia:: a naturalistic case-series outcome study

The glutamate hyperfunction hypothesis of schizophrenia has been proposed largely on the basis of studies in post-mortem brain and the lack of efficacy of glutamate agonists as antipsychotic drugs. Recent reports have also suggested that the addition of lamotrigine, a glutamate excess release inhibitor, can cause a dramatic improvement in clozapine treatment-resistant patients, as well as attenuate the neuropsychiatric effects of ketamine in healthy volunteers. To explore the glutamate hyperfunction hypothesis, patients with schizophrenia who were treatment-resistant to current antipsychotic medications were augmented with either lamotrigine (n = 17) or topiramate (a glutamate kainate/α-amino-3-hydroxy-5-methyl-4-isoxazolaproprionate antagonist that potentiates GABA function) (n = 9) for 24 weeks. Patients receiving lamotrigine augmentation of clozapine had a significant decrease in Brief Psychiatric Rating Scale score after 2 weeks of treatment. There was no significant improvement when lamotrigine was added to risperidone, haloperidol, olanzapine or fluphenthixol. There was also no significant improvement observed with topiramate augmentation of clozapine, olanzapine, haloperidol and fluphenthixol. These preliminary data support previous evidence that lamotrigine is an effective augmentation agent for clozapine. Although limited by sample size, the findings also suggest glutamate hyperfunction in schizophrenia may have a presynaptic basis and that atypicals with low dopamine receptor occupancy may have antagonistic actions on glutamate function which confer additional antipsychotic activity.

Blockade of phencyclidine-induced effects by a nitric oxide donor

Phencyclidine (PCP) is widely used as an animal model of schizophrenia. The aim of this study was to better understand the role of nitric oxide (NO) in the mechanism of action of PCP and to determine whether positive NO modulators may provide a new approach to the treatment of schizophrenia. The effects of the NO donor, sodium nitroprusside (SNP), were studied in PCP‐treated rats. Following drug administration, behavioural changes and the expression of c‐fos, a metabolic marker of functional pathways in the brain, were simultaneously monitored. Acute PCP (5u2003mgu2003kg−1, i.p.) treatment induced a complex behavioural syndrome, consisting of hyperlocomotion, stereotyped behaviours and ataxia. Treatment with SNP (2–6u2003mgu2003kg−1, i.p.) by itself produced no effect on any behaviour studied but completely abolished PCP‐induced behaviour in a dose‐ and time‐dependent manner. PCP had differential regional effects on c‐fos expression in rat brain, suggesting regionally different patterns of neuronal activity. The most prominent immunostaining was observed in the cortical regions. Pre‐treatment with SNP blocked PCP‐induced c‐fos expression at doses similar to those that suppress PCP‐induced behavioural effects. These results implicate the NO system in the mechanism of action of PCP. The fact that SNP abolished effects of PCP suggests that drugs targeting the glutamate‐NO system may represent a novel approach to the treatment of PCP‐induced psychosis and schizophrenia.

Lack of phencyclidine-induced effects in mice with reduced neuronal nitric oxide synthase

Abstract.Rationale: Phencyclidine (PCP) is widely used as an animal model of schizophrenia, because in humans it can induce positive and negative symptoms associated with schizophrenia. PCP is an antagonist of N-methyl-D-aspartate receptors, which are associated with the nitric oxide (NO) system. Objective and methods: The primary objective was to determine whether neuronal NO synthase (nNOS) is involved in PCP-induced behaviours and neuronal activation, as measured by the expression of c-Fos. After characterizing a PCP mouse model (dose-response study, Experiment 1), we measured PCP-induced effects in mice treated with nNOS antisense oligodeoxynucleotides (AS-ODNs) (Experiment 2), and in nNOS knockout (nNOS–/–) mice (Experiment 3). Results: PCP 5xa0mg/kg induced the maximum behavioural effects of all doses tested, consisting of hyperlocomotion, stereotyped turning behaviour, without the presence of ataxia. PCP also induced an increase in Fos-like immunoreactivity (Fos-LIR) in the frontal cortex, as well as in the midline limbic (thalamic and hypothalamic nuclei) areas. In the AS-ODN-treated mice, PCP induced less behaviour when compared to water-treated controls. In the nNOS–/– mice, PCP induced less behaviour and a decrease in Fos-LIR in the frontal cortex and midline limbic areas, when compared to wild-type littermate controls. Conclusions: Our findings suggest that the frontal cortex and midline thalamic brain regions are involved in PCP-induced effects in mice. Furthermore, we show that an intact nNOS system is necessary to obtain PCP-induced effects. This may implicate nNOS as a viable drug target in the treatment of schizophrenia.

Effects of nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester on phencyclidine-induced effects in rats

Phencyclidine (PCP) is widely used as an animal model of schizophrenia. In rats, acute PCP treatment increased locomotor activity and induced stereotyped behaviours consisting of head weaving, turning and backpedalling. PCP had differential regional effects on c-fos expression in rat brain, suggesting different patterns of neuronal activity. The most prominent immunostaining was observed in the cortical regions. To elucidate the role of nitric oxide, an important intracellular messenger, in the mechanism of action of PCP the effects of nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) were studied in PCP-treated animals. L-NAME potentiated PCP-induced behaviours and c-fos expression in many brain regions. The greatest increases were observed in the frontal, retrosplenial granular cortex, cerebellum, thalamic and subthalamic nuclei. While PCP alone induced low c-fos expression in the entorhinal cortex, with almost no expression in the rostral part of caudate putamen, animals pretreated with L-NAME showed marked activation in these brain areas. These results strongly indicate the involvement of the nitric oxide system in the mechanism of action of PCP.

Maintained improvement with minocycline of a patient with advanced Huntington's disease

We present the case of a patient with advanced Huntingtons disease treated with minocycline. Minocycline (but not tetracycline which does not cross the blood–brain barrier) appears to increase longevity in an animal model for Huntingtons disease. The patient has been maintained on minocycline for more than 1 year with positive effects. Cessation of minocyclin for 3 weeks resulted in an exacerbation of symptoms. The animal studies have suggested that minocycline may prevent progression of Huntingtons disease and other neurological disorders. By contrast, this present result suggests that minocycline may benefit those with advanced Huntingtons disease and can be used safely in these patients.

Neuroanatomy of coprolalia in Tourette syndrome using functional magnetic resonance imaging

OBJECTIVEnTo determine the neural substrates of phonic tics in Tourette syndrome (TS) using functional magnetic resonance imaging (fMRI) and compare with a proposed tic-generating network (TGN).nnnPATIENTSnOne with TS and one normal control.nnnMETHODSnfMRI scans were obtained on the TS patient during which numerous unsuppressed phonic tics occurred and, along with the scanner noise, were recorded on audiotape. The control underwent the same functional MRI sequence but mimicked the tics within predetermined, on-off time blocks. Fuzzy clustering (FC) methods were used to generate the activation maps.nnnRESULTSnThe TS patient and control showed fMRI activation in the left middle frontal gyrus and right precentral gyrus. The TS patient also had activity in the caudate nucleus, cingulate gyrus, cuneus, left angular gyrus, left inferior parietal gyrus, and occipital gyri.nnnCONCLUSIONSnfMRI, using an FC analysis, is a viable technique for studying TS patients with phonic tics. These results give further support to the hypothesis of a tic-generating circuit model. Further studies are required to confirm our data.

Noradrenergic and Serotonergic Neuroendocrine Responses in Prepubertal, Peripubertal, and Postpubertal Rats Pretreated With Desipramine and Sertraline

OBJECTIVEnTo explore whether developmental status of neurotransmitter systems may affect response to antidepressant treatment. This study investigated whether younger animals, compared with mature animals, showed the same neuroendocrine response to challenge drug probes when pretreated with a serotonergic or noradrenergic antidepressant.nnnMETHODnPrepubertal, pubertal, and adult rats were pretreated with low- or high-dose sertraline or desipramine for 14 days. Animals were then challenged with a noradrenergic probe (clonidine for desipramine-treated animals) or a serotonergic probe (fenfluramine for sertraline-treated animals). The neurohormonal response of growth hormone to the clonidine challenge and prolactin to the fenfluramine challenge was then measured.nnnRESULTSnIn animals challenged with fenfluramine, the postpubertal control group showed a significantly higher prolactin response to fenfluramine than postpubertal animals pretreated with low- or high-dose sertraline. No differences were found in the pubertal or prepubertal group. In animals challenged with clonidine, there was a significant age by treatment interaction effect for the prepubertal group pretreated with high doses of desipramine (less growth hormone secretion) but not for the peri- or postpubertal groups.nnnCONCLUSIONSnThese data indicate neurodevelopmental factors may play a role in the functional physiology of neurotransmitter systems, which in turn may affect response to psychotropics.

Effects of clozapine plus lamotrigine on phencyclidine-induced hyperactivity

There is growing evidence from both uncontrolled and controlled clinical studies that lamotrigine (LTG) significantly augments clozapine (CLZ) in the treatment of refractory schizophrenia (RS) [Dursun, S.M., McIntosh, D., Milliken, H., 1999. Clozapine plus lamotrigine in treatment-resistant schizophrenia. Arch. Gen. Psychiatry 56, 950; Dursun, S.M., Deakin, J.F.W., 2001. Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study. J. Psychopharmacol. 15, 297-301; Tiihonen, J., Hallikainen, T., Ryynanen, O.P., Repo-Tiihonen, E., Kotilinen, I., Eronen, M., Toivonen, P., Wahlbeck, K., Putkonen, A., 2003. Lamotrigine in treatment-resistant schizophrenia; a randomized placebo-controlled cross over trial. Biol. Psychiatry 54, 1241-1248; Kremer, I., Vass, A., Gorelik, I., Bar, G., Blanaru, M., Javitt, D.C., Heresco-Levy, U., 2004. Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Biol. Psychiatry. 56, 441-446]. However, the precise mechanism of action of this synergistic augmentation between clozapine and lamotrigine remains unclear. Therefore, the goal of this research is to explore the mechanism of action of this synergistic interaction between CLZ and LTG, utilizing a pharmacological animal model of schizophrenia by using phencyclidine (PCP). The effects of CLZ plus LTG were assessed by measuring PCP-induced hyper-locomotion and stereotyped behaviours in rats. Adult male rats (250-300 g) were pre-treated via intra-peritoneal (i.p.) injection with vehicle or drug 30 min before a PCP (5 mg/kg) or saline challenge. The behaviours were recorded and analysed for a 90-min period using the Etho Vision-computer based system. PCP produced hyper-locomotion, which was maximal at 30 min. LTG (10 mg/kg) significantly increased hyperlocomotion induced with PCP. However, a combination treatment of CLZ (5 mg/kg) plus LTG (10 mg/kg) significantly blocked the potentiation of PCP-induced hyper-locomotion observed with LTG (10 mg/kg) alone. Furthermore, the PCP-induced locomotion in the combination CLZ plus LTG-treated rats was significantly decreased when compared to vehicle. Therefore, LTG at doses that do not induce ataxia enhanced PCP-induced hyper-locomotion in rats, whereas the combination of LTG and CLZ significantly decreased PCP-induced hyper-locomotion consistent with clinical data.

Effects of ageing on prefrontal temporal cortical network function in healthy volunteers as assessed by COWA. An exploratory survey.

The prefrontal temporal cortical network (PFTCN) is a crucial part of a widely distributed neural network which has been shown (a) to subserve language function; (b) to modulate the cognitive circuits that are linked with work production; and (c) to organise thinking and develop word-search strategies. Dysfunction of the PFTCN has been reported in very early states of the dementing process. However, the functional state of the PFTCN during ageing in healthy volunteers remains unclear. Therefore, in this study, we investigated the effects of ageing, total years of education and use of caffeine and nicotine on Controlled Word Association Test (COWA) performance, a measure of PFTCN function. All subjects were mentally and physically healthy based on self-report and history, and were free of any medication at the time of the test. The COWA (also known as the Verbal Fluency Test or the FAS test) was used to investigate the functional state of the PFTCN. The total score is presented as the sum of all acceptable words generated. Multiple regression analysis was used to analyse the data. COWA scores did not correlate with caffeine or nicotine intake. However, there was a significant linear relationship between total years of education and COWA scores. Age-related changes were noted. A significant quadratic trend was observed in which subjects at both extremes of the age spectrum demonstrated poorer COWA performance. Due to limitations of our data, findings are suggestive of this trend in females but inconclusive vis a vis a possible ageing-related effect for males. These results might suggest that normal ageing-related changes as they involve the PFTCN are observed in females and, pending further studies, may differentially affect males and females. Furthermore, demographic variables such as education must be taken into account in studies in which the COWA is used. However, further studies are required in order to investigate the functional state of the PFTCN in dementia-related disorders.

Effects of amphetamine on saccadic eye movements in man : possible relevance to schizophrenia?

The antisaccade task can be used to test the voluntary control of saccadic eye movements (SEMs). In many disorders with postulated hyperdopaminergic neurotransmission, there are reports of abnormalities in SEMs. To further investigate this, the role of dopamine in SEMs, performance on an antisaccade task was examined in subjects with a history of amphetamine use (a dopamine releaser and reuptake inhibitor). A prospective design was employed in a teaching hospital setting. Six subjects (five males) with a history of amphetamine use were compared to 24 normal controls. None of the subjects were using any other substances, except alcohol and nicotine, as determined by urine screening, which we believe limited the sample size. For subjects who used amphetamine before the task, the presence of amphetamine was confrmed by urinalysis. All subjects completed the antisaccade task. Both error rates and latency rates during the antisaccade task were compared between the amphetamine users and controls. The amphetamine users had signifcantly increased error rates and latencies. These results may suggest that increased error rates and latencies during antisaccade tasks may be due to increased dopamine transmission, which is similar to the fndings in schizophrenia.