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Biomedical subjects

S M Dursun

Publications and source records attributed to S M Dursun.

At least 19 recordsLinked to original sources
PubMed2001

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

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 5 mg/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.

Animals↗
PubMed2001

Effects of antidepressant treatments on first-ECT seizure duration in depression.

1. Current guidelines on the practice of Electroconvulsive Therapy (ECT) suggest that antidepressant medications should be discontinued prior to the course of therapy. However, the practice of withholding potentially helpful medication is debatable because the effects of these medications on seizure duration remain unclear. In particular, there is a lack of empirical knowledge about the effects of Selective Serotonin Reuptake Inhibitors (SSRIs) on ECT treatment. 2. Therefore, we investigated and compared the effects of SSRIs and tricyclic antidepressants (TCAs) on seizure duration after the first bilateral ECT treatment. 3. The diagnosis of major depressive disorder was made using the DSM-IV criteria. Both patient groups were age- and sex-matched. ECT was indicated for acute suicidal acts or refractoriness to medications. All patients had received antidepressant treatment for at least eight weeks and were receiving at least the recommended dose of medication. All patients were ECT treatment-naïve and we measured the seizure duration after the first bilateral ECT treatment. 4. There was no significant difference between electrical charge applied to either group. Between the TCA and SSRI group the seizure duration was not significantly different: 33.2 seconds and 31.4 seconds respectively.

Adult↗
PubMed2001

An exploratory approach to the serotonergic hypothesis of depression: bridging the synaptic gap.

In this exploratory review, we attempt to integrate pre and post synaptic theories of the biochemical basis of depression--in particular with regard to 5-HT. We will be providing evidence that in major depressive disorder, there is a continuity of dysfunction of neural function, i.e. pre and post synaptic serotonergic symptoms are affected. Furthermore, we will also be providing the implications of this approach for normal treatments for depressive disorder.

Antidepressive Agents↗
PubMed2001

The 'dalhousie serotonin cocktail' for treatment-resistant major depressive disorder.

We describe the successful treatment of five patients with treatment-resistant major depressive disorder (TR-MDD) with a combination pharmacotherapy of pindolol, tryptophan and nefazodone. Five TR-MDD outpatients who had previously not responded to at least four different antidepressant medication trials were initiated on 300 mg/day of nefazodone, 7.5 mg/day of pindolol and 1 g/day of tryptophan. Pindolol doses remained the same throughout the 20 weeks, while tryptophan and nefazodone dosages were gradually increased to 8 g/day and 450 mg/day, respectively. The Hamilton Depression Rating Scale (HAM-D) was used to evaluate outcome. By week 4, all cases demonstrated at least 50% decrease in HAM-D scores. At the end of the trial, the group mean HAM-D score had significantly decreased from 26.8 (+/- 1.9) to 1.8 (+/- 0.8) (p < 0.001). No significant adverse effects were reported. These results suggest that if serotonin availability and release is further enhanced by tryptophan in the presence of nefazodone and pindolol, an antidepressant effect may be produced in patients who are otherwise treatment-resistant. Due to limited sample size, an open design and an 'unusually' high successful efficacy rate of this preliminary study, controlled studies are required to confirm the efficacy of this treatment strategy.

Adrenergic beta-Antagonists↗
PubMed2001

Antidepressant discontinuation (withdrawal) symptoms presenting as 'stroke'.

We report two patients who developed a severe discontinuation (withdrawal) reaction following stoppage of paroxetine and venlafaxine, respectively. Neurological symptoms were prominent and neither patient could walk unaided. Both patients feared they had suffered a 'stroke' and arranged an emergency medical consultation. One patient was correctly diagnosed, the antidepressant was recommenced and symptoms resolved within 24 h. Failure to recognize the reaction resulted in the other patient being referred to a neurologist, undergoing a computed tomography brain scan and an electroencephalogram and remaining symptomatic for over 8 weeks. Relevant pharmacological issues are discussed. The cases illustrate the importance of patients and clinicians being familiar with antidepressant discontinuation symptoms.

Adult↗
PubMed2001

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/alpha-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.

Adult↗
PubMed2000

Effects of nitric oxide synthase inhibitor N(G)-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.

Animals↗
PubMed2000

The effects of antipsychotic medication on saccadic eye movement abnormalities in Huntington's disease.

1. The study was a prospective open trial done to determine the effect of antipsychotic medication on saccadic eye movements in patients with Huntington's disease (HD). The authors tested 16 outpatients with HD, 8 of whom were drug free and 8 of whom were on antipsychotic medication. We also tested 24 healthy control subjects. 2. The antisaccade task was used to investigate the voluntary control of saccadic eye movements. Antisaccade latencies and error rates were used as outcome measures. Both HD patient groups showed significantly more antisaccade abnormalities than controls and the rate of abnormalities was very similar between the drug-free and medicated patient groups. 3. The results suggest that these abnormalities are related to underlying neuropathology rather than effects of medication. Either specific dysfunction of the dorsolateral prefrontal cortex or of the subcortical circuit connecting this cortical area to the superior colliculus via the striatum are likely to be responsible for the generation of such antisaccade eye movement abnormalities.

Adult↗
PubMed2000

Blockade of phencyclidine-induced effects by a nitric oxide donor.

1. 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. 2. 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. 3. Acute PCP (5 mg kg(-1), i. p.) treatment induced a complex behavioural syndrome, consisting of hyperlocomotion, stereotyped behaviours and ataxia. Treatment with SNP (2 - 6 mg kg(-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. 4. 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. 5. 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.

Animals↗
PubMed2000

An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria.

Serotonin-related adverse side-effects of psychotropic drugs were first recorded in humans in 1960. However, since 1991, these related cases have been diagnosed as 'serotonin syndrome (SS)' according to the criteria reported by Sternbach. In this article, we have reviewed and further explored the validity of these criteria. The clinical profile of 24 cases of the SS published between 1991 and 1995 has been analysed in detail and compared with the symptomatology of 38 previous cases which were also further analysed. Mainly Medline and references from other reports were used to review these cases. The general concept put forward by Sternbach has been approved. On the basis of the severity of overall clinical presentation, it appeared that there is a need to further classify SS into three main groups as: (1) mild state of serotonin-related symptoms; (2) serotonin syndrome (full-blown form); (3) toxic states. Furthermore, the detailed analysis of the SS cases published so far suggests that 'the diagnostic criteria for SS' also require further revision, and these are presented here. We also review, present and discuss the guidelines for the management and treatment of SS.

Humans↗