Journal of Psychopharmacology

Neurotransmitter receptors play a key role in most research on antipsychotic drugs, but little is known about the effects of these drugs on the plasma membrane in the central nervous system. Therefore, we investigated whether chlorpromazine (CPZ), a typical phenothiazine antipsychotic drug, affects the plasma membrane integrity in the rat brain, and if so, whether these membrane alterations can be prevented by dietary supplementation with vitamin E, which has been shown to be an antioxidant and also a membrane-stabilizer. Leakage of [¹⁸F]2-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG)-6-phosphate from rat striatal slices and decrease in 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy were used as indexes for plasma membrane permeabilization and fluidization, respectively. CPZ induced leakage of [¹⁸F]FDG-6-phosphate from striatal slices, and the leakage was delayed in the vitamin E-supplemented group compared to that in the normal diet group. The decrease in plasma membrane anisotropy induced by CPZ was significantly attenuated by vitamin E supplementation. Chronic treatment with α-phenyl-N-tert-butyl nitrone, a free radical scavenger, had no effect on CPZ-induced plasma membrane permeabilization, and the treatment with CPZ did not induce lipid peroxidation. CPZ can reduce plasma membrane integrity in the brain, and this reduction can be prevented by vitamin E via its membrane-stabilizing properties, not via its antioxidant activity.

Risperidone long acting injection (RLAI) is the only long acting atypical antipsychotic available in the UK. Its impact on NHS resource use has not been widely studied. This review of medical records was conducted to quantify the impact of RLAI on NHS psychiatric secondary care resource use, primarily in terms of episodes of inpatient hospital care 12 months before and 12 months after RLAI initiation. Data on number of hospitalizations and hospital bed days were collected retrospectively, from patient notes and hospital databases in four acute psychiatric units in the UK for all individuals with a diagnosis of schizophrenia or schizoaffective disorder who were prescribed RLAI more than 12 months previously. Data were collected on 100 individuals (58 male) with a mean age 40.8 years (range 19—70). The median duration of illness before RLAI initiation was 12 years (range six months to 43 years).

There were 62 admissions in the 12 months pre-RLAI, falling to 22 admissions in the 12 months post-RLAI. Number of admissions, we argue, offer a more reliable indicator of the impact of treatment than total hospital bed days in this type of study. In this study there were 40 fewer admissions in the 12 months after RLAI was initiated compared with the previous 12 months. This is important as readmission is a good proxy measure of relapse, and adherence to medication is known to be a key factor in relapse prevention.

Escitalopram is a highly selective inhibitor of serotonin re—uptake that is used to treat anxiety disorders. In the present study, we investigated the effects of acute, sub-chronic (14 days) and chronic (21 days) administration of escitalopram (2, 4 and 8 mg/kg, PO) on the performance of rats in the elevated T-maze. For comparison, imipramine (15 mg/kg, PO) was also studied. The apparatus is made of three elevated arms of equal dimension, one enclosed transversal to the two open arms. Inhibitory avoidance of the open arms, trained in the enclosed arm, has been related to generalised anxiety disorder, while one-way escape from one open arm, to panic disorder. After acute administration, the three doses of escitalopram impaired avoidance (anxiolytic effect), while imipramine was ineffective. Escape was unaffected by either drug. With subchronic administration, both drugs were ineffective on either avoidance or escape. After chronic treatment, avoidance was impaired by imipramine and by the two highest doses of escitalopram. In addition, escape was impaired (panicolytic effect) by imipramine and by the highest dose of escitalopram. Locomotion measured in a square arena was increased by the three doses of escitalopram, given chronically. Therefore, both imipramine and escitalopram had anxiolytic and panicolytic-like effects after chronic administration, but acutely only escitalopram decreased anxiety. Since no such effect was observed following subchronic administration, it is likely that the mechanisms of the early and late anxiolytic actions of escitalopram are different.

Deficits in response inhibition are a prominent feature of Bipolar Disorder, type I (BDI). The purpose of this study was to examine the relationship between inhibitory control and cerebral structure as it may inform our understanding of the pathophysiology of BDI. Inhibitory control was measured in remitted patients with BDI (n = 44) and healthy controls (n = 44), using the interference score from the Stroop Colour Word Task and the scaled total error score from the Hayling Sentence Completion Test. Structural magnetic resonance imaging brain scans were also obtained for all participants. For both measures, better performance in controls correlated positively with gray matter volume in the dorsal and ventral prefrontal cortical (PFC) regions with parietal involvement additionally seen for the interference score. In contrast, better inhibitory control in BDI patients correlated positively with gray matter volume in the right parietal cortical regions, namely the cuneus for the scaled total error score and the inferior parietal lobule for the interference score. The observed lack of correlation between PFC grey matter and measures of inhibitory control in BDI patients is suggestive of PFC dysfunction; the correlation between response inhibition and parietal grey matter volume may be indicative of a compensatory involvement of the parietal cortices in BDI.

Experimental and clinical studies have supported a relationship between γ-aminobutyric acid (GABA) and aggressive behavior in non-humans and humans. Tiagabine is a GABA uptake inhibitor that has been shown to produce acute behavioral effects in animals. In addition, tiagabine has been shown to decrease aggression in agitated patients when administered chronically. The present study was designed to investigate the effects of acute administration of tiagabine on aggressive responding on a laboratory task in adult humans. Ten adult males participated in experimental sessions on the Point Subtraction Aggression Paradigm (PSAP), which provided subjects with aggressive, escape, and monetary-reinforced response options. All subjects received four acute oral doses of Tiagabine (4, 8, 12 and 16 mg) separated by placebo sessions. Tiagabine decreased aggression at doses that either did not affect, or affected to a lesser extent, monetary-reinforced responding. The results are consistent with some prior research using the PSAP showing a possible unique role for GABA in the regulation of human aggression. A possible behavioral mechanism for the rate-decreasing effects on aggressive responding produced in the present study is that tiagabine may modify aggressive responding by suppressing reactions to aversive stimuli.

Guidelines for treating depression often recommend continuing antidepressants at least for 6 months after remission. Whether this recommendation is implemented in daily practices represents a serious concern. We aimed to examine adequacy of continuation and maintenance treatment in Japan. A naturalistic prospective follow-up study with mood disorders was undertaken in 23 psychiatric departments from all over Japan. A total of 95 patients diagnosed with major depression were followed up every month until treatment termination and every 6 months thereafter. In this study, the cohort received 45.1 (SD = 64.7) mg of imipramine or equivalent per day during continuation phase, and about 74% were prescribed inadequate doses, i.e. less than 75 mg/day. At maintenance phase immediately before relapse, average dosage was 42.0 (SD = 74.7) mg/day and 83% were prescribed inadequate doses. There is gross under-treatment of depression during continuation and maintenance phases in Japan.

Objective: To assess the efficacy and safety of escitalopram in treating specific phobia. Method: The study was performed in an academic medical center. Adults meeting DSM-IV criteria for specific phobia were randomly assigned to 12 weeks of double-blind treatment with escitalopram or placebo. Efficacy measures included the Main Phobia Scale (MPS), the Marks Fear Questionnaire (FQ) and the Clinical Global Impressions of Improvement (CGI-I) scale. Data were collected between September 2002 and September 2004. Results: Of 13 subjects enrolled, 12 returned for at least one post-randomization visit and were included in the intent to treat sample. Response rates on the various subscales of the MPS and the FQ ranged from 20 to 80% for escitalopram, compared to 0—43% with placebo. Rates of response using the CGI-I scale were 60% for escitalopram and 29% for placebo, with a strong between treatment effect in favor of the drug at week 12 (effect-size = 1.13). Using the last observation carried forward, no statistically significant treatment differences were found. The drug was well tolerated. Conclusion: Treatment response was consistently greater for escitalopram than for placebo, with strong effects observed in favor of the drug. However, treatment differences on the primary outcome measures were not significant in this under-powered pilot study. Escitalopram may hold promise as a treatment for specific phobia and larger randomized controlled trials are needed.

Present study was designed to investigate modulation of experimental dementia by Pitavastatin and donepezil. Learning and memory of the swiss albino mice were studied on Morris water-maze. Celecoxib orally (p.o.)/Streptozotocin (STZ) intracerebroventricular administrations were used to induce experimental dementia. Brain acetyl cholinesterase activity was measured by EllMann's method to assess cholinergic activity of the brain. Brain thio barbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured by Ohokawa's and Beutler's method respectively, to assess total oxidative stress in brain. Total serum cholesterol level was measured by Allain's method. Celecoxib/STZ treatments produced a significant loss of learning and memory. Pitavastatin/Donepezil successfully attenuated this Celecoxib/STZ induced dementia. Higher levels of brain acetyl-cholinesterase (AChE) activity, TBARS and lower level of GSH were observed in Celecoxib/STZ treated animals, which were significantly attenuated by Donepezil. Pitavastatin also attenuated the Celecoxib/STZ induced high levels of TBARS & low levels of GSH without effecting AChE activity and total serum cholesterol levels. Celecoxib induced dementia noted in the present study may be attributed to its stimulatory effect on amyloid beta-42, brain AChE activity, and oxidative stress. Sub-diabetogenic STZ induced memory deficits closely related to Alzheimer's disease. Reversal of Celecoxib/STZ induced memory deficits by Pitavastatin may be due to its antioxidative, anti beta amyloid aggregatory property, and by Donepezil, due to its anticholinesterase and neuroprotective actions.

There is evidence that the indirect dopamine (DA) agonist amphetamine (AMP) can disrupt selective learning in an aversive overshadowing task, consistent with a role for the DA system in this form of salience manipulation. In the following experiments we assessed in the male Wistar rat: (1) whether amphetamine disruption of overshadowing extends to an appetitively motivated overshadowing task; and (2) whether selective electrolytic lesions to the n.acc (shell versus core subfields) disrupt appetitively motivated overshadowing. The experiments used sucrose reward pellets as the unconditioned stimulus (UCS). In each case, a conditioned stimulus (CS, light) was either conditioned alone or in compound together with a more intense CS (noise or tone). The presence of overshadowing was demonstrated as reduced conditioning to the light when it had been previously conditioned in compound compared to when it had been conditioned alone.

It was predicted that AMP and lesions to the n.acc shell would disrupt overshadowing. AMP was found to abolish overshadowing at 0.5 mg/kg, but not at 1 mg/kg. Contrary to prediction, the shell lesioned animals did not differ from shams. The results of Experiment 1 add to the evidence that the DA system can moderate salience processing of weaker predictors, also in cases where CS salience is manipulated directly via the physical intensities of the stimuli, as here. However, in terms of the brain structures involved, Experiment 2 suggests that, overshadowing is moderated by projections of the DA system without n.acc.

Atypical antipsychotic drug therapy may result in substantial weight gain, increased adiposity and the promotion of metabolic abnormalities. The mechanism(s) which underlie such effects remain unclear. Previous studies in our laboratory have demonstrated significant weight gain in female rats maintained on a standard laboratory diet after sub-chronic administration of olanzapine and risperidone, but not ziprasidone. The aim of this paper is to investigate the effect of antipsychotic drugs on body weight, ingestive behaviour and adiposity in female rats with access to a high fat diet. Adult female rats given free access to a high fat diet received either olanzapine (2 mg/kg), risperidone (0.5 mg/kg), ziprasidone (2.5 mg/kg) or vehicle for 28 days. Body weight, food and water intake in addition to intra-abdominal fat deposition were assessed. Olanzapine initially increased body weight but by the end of the study olanzapine animals appeared to have lost weight compared to the vehicle-treated group. Olanzapine-induced reductions in body weight were accompanied by a significant hypophagia during weeks 3 and 4. Risperidone increased body weight during week 1 only and reduced intake of a high fat diet during weeks 3 and 4. Ziprasidone was without effect on indices of body weight and ingestive behaviour. There were no effects of antipsychotic drugs on intra-abdominal fat deposition. Access to a diet high in fat attenuated weight gain induced by olanzapine and risperidone in female rats.

Human MDMA (R,S-3,4-methylenedioxymethamphetamine) users display selective cognitive deficits after acute MDMA exposure, frequently attributed to serotonin deficits. We postulated that MDMA will compromize executive function in primates and that an inhibitor of the serotonin transporter (SERT) and the norepinephrine transporter (NET) but not the dopamine (DAT) transporter, will prevent impairment. The potencies of DAT/NET, NET and SERT inhibitors to block transport of [³H]MDMA and [³H]monoamines were compared in vitro. Subsequently, cynomolgus monkeys (Macaca fasicularis) were trained to stable performance in a reversal learning task. Effects of once-weekly oral or i.m. dose of MDMA (1.5 mg/kg, n = 4) on performance were monitored, alone or after pretreatment with inhibitors of the SERT, DAT or NET (prior to i.m. MDMA). 1) Drug potencies for blocking [³H]MDMA or [³H]monoamine transport were not consistent; 2) Oral MDMA increased error rates in a cognitive task for up to three days following exposure, whereas intramuscular MDMA prevented subjects from performing the cognitive task on the day of administration, but not on subsequent days; 3) The SERT inhibitor citalopram and the NET inhibitor desipramine, but not the DAT/NET inhibitor methylphenidate, reversed the effects of MDMA on task performance and mandibular movements induced by i.m. MDMA and 4) MDMA altered sleep latency. Oral MDMA impairs executive function in monkeys for several days, a finding of potential relevance to MDMA consumption by humans. Reversal of impaired executive function by a NET inhibitor implicates the NET and norepinephrine in MDMA-induced cognitive impairment and may be relevant to therapeutic strategies.

It has been previously demonstrated that unmedicated persons with schizophrenia have deficits in cortical inhibition (CI) as indexed with transcranial magnetic stimulation (TMS). This inhibition is largely mediated by cortical GABAergic mechanisms. It has also been demonstrated that these inhibitory deficits may be normalized with the use of atypical antipsychotic medications. The purpose of this study, therefore, was to examine the effects of clozapine on TMS measures of CI and to compare these effects to unmedicated persons with schizophrenia and healthy subjects. We used two TMS inhibitory paradigms: short interval intra-cortical inhibition (SICI) and the cortical silent period (CSP) to evaluate CI in 10 clozapine-treated persons with schizophrenia, 6 unmedicated persons with schizophrenia and 10 healthy subjects. Clozapine-treated persons with schizophrenia had significantly longer CSPs compared with healthy subjects and unmedicated persons with schizophrenia. There were no significant differences in SICI between groups, however, the severity of psychotic symptoms was correlated with reduced SICI across all persons with schizophrenia. Our findings suggest that clozapine treatment is associated with greater CI in persons with schizophrenia and this increase may be related to potentiation of cortical GABAergic receptor mediated inhibitory neurotransmission. Our results also confirm previous findings suggesting that deficits in CI are related to the severity of psychotic symptoms in persons with schizophrenia.

Obsessive compulsive disorder (OCD) is a chronic disorder, currently recognized as one of the most common psychiatric disorder as well as one of the most disabling of all medical disorders. OCD is characterized by high rates of partial and/or absent response to standard, recommended treatments (serotonin reuptake inhibitors and psychotherapy). Recent investigation showed that Venlafaxine, a dual serotonin and norepinephrine reuptake inhibitor (SNRI), may be a valid alternative for some treatment-refractory patients. We present the cases of four OCD patients with comorbid mood or anxiety disorders, who were treated with serotonin reuptake inhibitors (SRIs) at adequate doses for at least 12 weeks, showing partial/no response. Patients were then switched to Duloxetine up to 120 mg/day and followed up for 12 weeks. Three out of four patients showed a Yale-Brown Obsessive Compulsive Scale

(Y-BOCS) score reduction ≥35%. Duloxetine may be helpful in patients with treatment-resistant OCD, although larger and controlled studies are warranted to confirm this preliminary observation.

Although venlafaxine is usually associated with modest increases in blood pressure and not so often clinical hypertension, there are a few reported cases of hypotension related to overdoses of this specific antidepressant. The case study of a young female patient with a history of Major Depressive Disorder who initiated treatment with venlafaxine 75 mg/day and developed hypotension when the dosage was titrated up to 225 mg/day is described. The patient did not present comorbid diseases nor use other medication. A temporal association and a dose-dependent relationship between the hypotension and the use of venlafaxine is shown. To the best of the knowledge of the authors,

this is the first case report that specifically associates regular doses of venlafaxine with the presence of hypotension. A pathophysiological mechanism is proposed, involving the participation of presynaptic alpha2-adrenergic receptors and the presence of a possible genetic polymorphism of cytochrome P4502D6, which is associated with lower drug metabolization, to explain the relationship between venlafaxine in regular dosage and development of hypotension.