The effects of alpha 2-adrenoceptor antagonists on the inhibition of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head shakes by 5-HT1A receptor agonists in the mouse.

1. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), gepirone, buspirone and ipsapirone dose-dependently antagonized the head-shakes induced by 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane hydrochloride (DOI) (1.0 mg kg-1) in mice, when these agents were given i.p. 10 min beforehand. 2. para-Chlorophenylalanine (pCPA) abolished the effect of 8-OH-DPAT (0.1 mg kg-1) and of buspirone (1.0 mg kg-1). (+/-)-Pindolol (5.0 mg kg-1) also antagonized the effect of 8-OH-DPAT (0.1 mg kg-1). 3. The alpha 2-adrenoceptor antagonists, RX811059 (1.0 mg kg-1), idazoxan (0.5 mg kg-1), yohimbine (1.0 mg kg-1) and 1-(2-pyrimidinyl)-piperazine (1-PP) (2.0 mg kg-1) i.p. prevented the antagonistic effect of 8-OH-DPAT (0.1 mg kg-1) on DOI-head-shakes. 4. Orally-administered buspirone, given 60 min beforehand, only reduced DOI-head-shakes at doses of 60 mg kg-1 and above. However, when buspirone (1.0 mg kg-1) was administered orally twice daily for 21 days, DOI-head-shakes were significantly reduced when tested 60 min after the first daily dose on days 5, 12 and 21 and 48 h after withdrawal. 5. A single oral dose of buspirone (1.0 mg kg-1) strongly antagonized DOI-head-shakes when given 24 h after the last of 4 daily doses of 1-PP (2.0 mg kg-1, p.o.) but had no effect on DOI-head-shakes 24 h after the last of 4 daily doses of water (p.o.). 6. A single oral dose of 1-PP (2.0 mg kg-1) abolished the inhibitory effect of i.p. buspirone(1.0 mg kg-1) on DOI-head-shakes in mice which had received water (p.o.) daily on the 4 previous days but not in mice which had received 1-PP (2.0mg kg-1, p.o.) on these days.7. The ability of 5-HT1A receptor agonists to antagonize DOI-head-shakes may be due to an effect at presynaptic 5-HT receptors. It is suggested that 1-PP, formed from buspirone, may act at a2-adrenoceptors to prevent acutely administered oral buspirone from antagonizing DOI-head shakes, but that tolerance occurs to this effect of I-PP, thus revealing the inhibitory effect of buspirone when the latter is given repeatedly.

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.

Similarities in the pharmacology of spontaneous and DOI-induced head-shakes suggest 5HT2A receptors are active under physiological conditions.

Nine monoamine receptor antagonists have been compared for their potency to inhibit both spontaneously occurring and DOI ((1-)2,5-dimethoxy-4-iodophenyl)-2-aminopropane)-induced head-shakes (HS). Ritanserin, ketanserin, prazosin, haloperidol, pimozide, SCH 23390 and SCH 39166 potently and dose-dependently antagonised both types of HS while sulpiride and raclopride produced weak and partial antagonism. The potency of these agents to inhibit spontaneous HS and DOI-induced HS was closely correlated (r = 0.94) and was significantly related to 5HT2A receptor and to alpha 1-adrenoceptor affinities taken from published sources. Potency was independent of affinity for D2 receptors but there was a possible influence of D1 receptor affinity. HS have been proposed to model Tourette's Syndrome; thus the present findings may have implications for the mechanism of action of antipsychotic agents in this condition and possibly also in schizophrenia. Contrary to previous suggestions, 5HT2A receptors may be tonically activated under physiological conditions.

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.

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.

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.

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.

Complex of rapid movements and vocalization induced by RX336-M in mice: possible relevance to Tourette's syndrome.

RX336-M (7,8-dihydro-5',6'-dimethylcyclohex-5'-eno-1',2',8',14 codeinone) induced a complex of simultaneous rapid movements of body parts accompanied by a single squeak-vocalization, which occurred at irregular intervals, when injected i.p. in mice. The complex included whole body jerks and head-shakes and its frequency was dose dependent between 0.1 and 20 mg/kg. Frequency after a 5 mg/kg dose was reduced by haloperidol (0.5-10 mg/kg, i.p.), ritanserin (0.1-10 mg/kg, i.p.) and ICI 169,369 (2.0 mg/kg, i.p.), suggesting the possible involvement of 5-HT(2A) and/or dopamine receptors. The possible relevance of the behavioural effects of RX336-M to the tics and vocalization of Tourette's syndrome is discussed.

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.

Improvement of abnormal saccadic eye movements in Huntington's disease by sulpiride: a case study.

Sulpiride treatment improved both the abnormal asymmetric saccadic eye movements (SEM) and the abnormal involuntary movements (AIMs) in a patient with Huntington's disease (HD). However, sulpiride corrected the abnormalities of SEM in the right, but not the left, hemi-field and the degeneration of the left striatal tissue was greater as visualised by the magnetic resonance imaging (MRI) scan.

A comparative trial use of sulpiride and risperidone in Huntington's disease: a pilot study.

Sulpiride and risperidone treatment significantly improved the abnormal involuntary movements of two patients with Huntington's disease on both actometer and clinical assessments. However, treatment with risperidone, but not sulpiride, significantly improved the functional activities as assessed by the Functional Disability Scale. To the best of our knowledge this is the first report of the successful treatment of Huntington's disease with risperidone.

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.

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.

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 confirmed 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 significantly 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 findings in schizophrenia.

Pimozide treatment of a male case with de Clerambault's syndrome and schizophrenia.

Effective treatment with pimozide of a male patient with secondary de Clérambault's syndrome (DCS) and schizophrenia is reported. There was no evidence of relapse at 24-month follow-up. Pimozide is suggested to be the drug of choice in DCS and may be in other disorders in which symptoms of erotomania are prominent. The unique anti-erotomanic activity of pimozide may be due to its calcium channel antagonist activity, a property which is not shared by the other antipsychotic drugs.

Successful treatment of urinary incontinence with clozapine in a schizophrenic patient.

There is evidence that urinary incontinence (UI) can develop without any organic aetiology as a direct side effect of typical antipsychotic medication. Clozapine was administered to a chronic schizophrenic patient with UI who was refractory to typical antipsychotic medication. After various laboratory and functional tests, UI was demonstrated to be unrelated to any organic aetiology. UI was monitored throughout the study as frequency (wetting the bed) per day and night. The Brief Psychiatric Rating Scale (BPRS) was also rated. Clozapine (dose-dependently) reduced both the BPRS score and frequency of UI, which were refractory to trifluoperazine and sulpiride. This is the first report of a dramatic resolution of UI in a schizophrenic patient after clozapine treatment. It is suggested that preference should be given to clozapine in such cases, since various other antipsychotic medications were ineffective and in some cases worsened the existing UI.

High-dose vitamin E plus vitamin B6 treatment of risperidone-related neuroleptic malignant syndrome.

We present a case of a 74-year-old patient with schizoaffective disorder, who developed risperidone-related neuroleptic malignant syndrome. This patient responded satisfactorily to the supportive management and vit E plus vit B6.

Antisaccade eye movement abnormalities in Tourette syndrome: evidence for cortico-striatal network dysfunction?

Saccadic eye movements are rapid eye movements which act to redirect the eyes from one object of interest to another. Accurately and objectively measurable, their underlying neuroanatomical mechanisms have been extensively studied. The antisaccade task allows the study of the frontocortico-striatal network involved in the voluntary control of saccadic eye movements. In this task, the subject is instructed to inhibit a reflex eye movement towards a peripheral target light and, instead, to generate a movement in the equal and opposite direction. An error occurs when the subject fails to suppress reflexive saccades towards the target. Significantly high error rates and increased latencies in the antisaccade task have been reported in disorders associated with dysfunction of the frontocortico-striatal network. Increased saccadic eye movement latencies and error rates have been reported in Tourette syndrome patients (n = 4) who were receiving antipsychotic medication. To investigate this further, we tested the antisaccade task on six male Tourette syndrome patients. The results were compared with 18 age- and sex-matched mentally and physically healthy, medication/alcohol-free controls. Antisaccade latencies were (mean +/- SD; ms) 751.2+/-186.7 for the Tourette syndrome group and 417+/-75.3 for controls, and error rates were 59+/-14.3 for the Tourette syndrome group and 11.9+/-6.4 for controls, respectively. These significant results may further support dysfunction of the frontocortico-striatal network in Tourette syndrome.

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

We present the case of a patient with advanced Huntington's 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 Huntington's 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 Huntington's disease and other neurological disorders. By contrast, this present result suggests that minocycline may benefit those with advanced Huntington's disease and can be used safely in these patients.