Journal of Psychopharmacology

Fear (e.g. associated with the threat of an electric shock) causes an increase in initial pupil diameter (IPD) and a decrease in the amplitude of the light reflex response. There is evidence for dissociation between the two responses to threat: only the reduction in light reflex response amplitude is sensitive to the anxiolytic drug diazepam. We examined the effects of peripheral sympathetic blockade with the α₁-adrenoceptor antagonist dapiprazole on both responses to threat on the basis of the hypothesis that only the response of the IPD will be affected, whereas the response of the light reflex will remain unaffected. Twelve healthy volunteers (Experiment 1) and eight healthy volunteers with smaller pupils (Experiment 2) participated in one experimental session. Dapiprazole 0.5% (two drops of 20 µl, three times) was instilled in the subjects’ right or left eye while the contralateral eye was treated with placebo eye drops (artificial tear, two drops of 20 µl, three times) according to a single-blind balanced design. Pupil diameter was monitored by infrared binocular television pupillometry. At the point of maximum dapiprazole-evoked miosis, the light reflex was elicited three times in each of three Safe blocks (no possibility of electric shock), alternating with three Threat blocks (possibility of electric shock). At the end of each Safe and Threat block, subjects rated their mood and feelings on the Visual Analogue Scales. In Experiment 1, dapiprazole caused significant miosis. Threat increased subjectively rated anxiety and inhibited the light reflex. The inhibition of the light reflex was unaffected by dapiprazole. The threat-induced increase in IPD was also unaffected by dapiprazole, probably due to a ceiling effect curtailing the threat-induced increase in IPD. In the smaller pupil group in Experiment 2, where the possible contribution of a ceiling effect was minimized, dapiprazole suppressed the threat-induced increase in IPD. The inhibition of the light reflex by threat is likely to reflect central parasympathetic inhibition and is unlikely to involve the peripheral sympathetic innervation of the iris. The threat-induced increase in IPD is likely to reflect mainly central sympathetic excitation. The different central autonomic mechanisms underlying the two pupillary responses to threat may explain the dissociation between the separate effects of threat on IPD and light reflex amplitude.

It is well known that modafinil is an effective wake-promoting agent, but there is growing evidence to suggest that modafinil may also enhance some aspects of cognition. In man, modafinil has been shown to enhance vigilance in sleep-deprived and/or narcoleptic subjects and also to improve executive-type functioning (predominantly inhibitory response control processes) across a variety of human patient population groups. Preclinically, a delay-dependent improvement has been reported with modafinil in a mouse T-maze test of working memory. To investigate further the role of modafinil as a potential cognition enhancer, the effects of modafinil on attentional processes were assessed in the rat. The aim of the present study was to evaluate the potential of modafinil to enhance five-choice serial reaction time test (5-CSRT) performance. Lister Hooded rats received 32-128 mg/kg modafinil and 5-CSRT performance was assessed under standard and test parametric conditions in which the attentional load was increased, and also under conditions of scopolamine pre-treatment. Modafinil failed to significantly enhance 5-CSRT performance under standard conditions. Similarly, modafinil was unable to reverse the deficits in accuracy and/or increased omission errors induced by either parametric or pharmacological manipulations. Indeed, at higher doses, modafinil caused an increase in premature responding under certain test conditions, suggestive of increased impulsivity. The present findings suggest that, although modafinil may enhance vigilance in sleep-deprived human subjects, attentional processes in normal awake rats remain unaffected. No evidence was found to support a modafinil-induced improvement in response control; rather, under conditions of increased attentional load, modafinil appeared to facilitate impulsive responding. Finally, the failure of modafinil to improve a scopolamine-induced performance deficit suggests that modafinil does not act on the cholinergic system directly.

Phenytoin (Dilantin®) is an anticonvulsant used in the treatment of epilepsy. It is believed to act by modulation of glutamatergic transmission. Because the neurobiology of post-traumatic stress disorder (PTSD) has been hypothesized to involve alterations in glutamatergic transmission with subsequention neurotoxicity, we assessed the effects of phenytoin on cognition and brain structure in PTSD patients. Phenytoin was administered in an open label fashion for 3 months to nine adult patients with PTSD related to a variety of traumas, including early abuse, combat and car accidents. Subjects underwent magnetic resonance imaging for measurement of whole brain and hippocampal volume, and neuropsychological testing of memory and cognition, before and after treatment. Phenytoin treatment resulted in a significant 6% increase in right brain volume (p < 0.05). Increased hippocampal volume was correlated with reductions in symptom severity as measured by the Clinician Administered PTSD Scale and improvements in executive function as measured by the Trails test. However, treatment associated improvements in memory and cognition did not achieve statistical significance. These findings suggest that phenytoin treatment may be associated with changes in brain structure in patients with PTSD.

In the context of a long-term follow-up study, we analysed the possible implication of the 5-HT_1A receptor gene (HTR1A) -1018C/G polymorphism in the clinical outcome of major depressive patients treated with citalopram. We had previously reported an association between variation on the SERT gene (SLC6A4) and clinical remission after citalopram treatment. In the present 12-week follow-up study, the combined effect of HTR1A and SLC6A4 genes in clinical outcome and response to citalopram was also evaluated. The sample consisted of 130 patients, all of Spanish origin, who were diagnosed as having a current major depressive episode according to DSM-IV criteria. A 21-item Hamilton Depression Rating Scale was used to assess severity of symptoms at the beginning and during the follow-up to determine the outcome and remission status at week 12. Patients were genotyped for HTR1A gene and, in addition, for two polymorphisms at the CYP2C19 gene, which together account for the 87% of the Caucasian poor metabolizer phenotype. Data were analysed adjusting for the effect of poor metabolizers in clinical response. No independent effect was found for the 5-HT_1A receptor gene in relation to clinical outcome or remission after citalopram treatment. However, a combined genetic effect of HTR1A and SLC6A4 genes was found to influence the clinical outcome of patients [F(4,102) = 2.89, p= 0.02]. When considering the remission status, an increase of patients carrying the risk genotype combination (S/S-G/G) was found among those subjects who did not reach remission (Fisher’s exact test = 0.009). Our results suggest that the combined effect of the serotonin transporter and the 5-HT_1A receptor genes could be related to the clinical outcome of depressive patients treated with citalopram.

Gingko biloba has cognitive benefits both in populations suffering from dementia and after acute treatment in healthy volunteers, with some evidence indicating that those with poorer cognitive performance show greater benefit. We have previously found that 1 week of treatment with ginkgo improved attention, memory and mental flexibility in post-menopausal women, but the evidence for any beneficial effects of longer treatment is less well-established. The present study aimed to determine whether cognitive benefits, similar to those previously found after 1 week of treatment, would persist after 6 weeks of treatment, and whether those with poorer cognitive performance would benefit more. In a placebo-controlled, double-blind study, postmenopausal women (aged 51-67 years) were randomly allocated to receive a standardized extract of ginkgo (LI 1370, Lichtwer Pharma, Marlow, UK) (one capsule/day of 120 mg, n = 45) or matching placebo (n = 42) for 6 weeks. According to an established reproductive staging system, subjects were divided into those in the early (Stage +1; mean age 55 years) and late (Stage +2: mean age 61 years) stages of menopause. At baseline and after 6 weeks of treatment, subjects completed tests of mental flexibility, planning, memory and sustained attention, and ratings of mood, sleepiness, bodily and menopausal symptoms. The only significant effects of ginkgo were in the test of mental flexibility, in which there were significant menopausal stage-ginkgo interactions. This was because subjects in Stage +2 required fewer trials to complete the task and made fewer errors after ginkgo treatment, whereas those in Stage +1 showed no benefits. Subjects in Stage +2 had poorer performance at baseline compared to those in Stage +1 both in this task and the test of planning ability. The beneficial effects of ginkgo were limited to the test of mental flexibility and to those with poorer performance.

The associations between psychosis, antipsychotic drugs and diabetes mellitus have not been precisely defined but it has been repeatedly suggested that atypical antipsychotics are more likely to give rise to diabetes than are conventional drugs. This belief is largely based on healthcare database analyses which, in part, rely on the assumption that all cases of diabetes are identified in practice. We examined records of 606 hospitalized patients receiving antipsychotic treatment and found an apparent prevalence of diabetes and impaired fasting glucose of 6.4%. From this sample of patients, we investigated 166 patients (fasting blood samples) who were not known to have any disorder of glucose homeostasis and identified 10 cases of impaired fasting glucose and nine cases of diabetes mellitus (11.4% of those tested). Nine of these cases had documented evidence of previous testing for diabetes. Apparent prevalence of diabetes and impaired fasting glucose was 16.9% in those tested in practice or the study. Diagnosis was significantly associated with age [odds ratio (OR) 1.02] and treatment duration with current drug (OR 1.01). Adjusted ORs of diagnosis were not significantly different for any atypical antipsychotic compared with conventional drugs. It is concluded that there was a clinically significant prevalence of undiagnosed diabetes and impaired fasting glucose in those individuals receiving antipsychotics. Importantly, database analyses may underestimate the true prevalence of diabetes in similar populations and erroneously ascribe increased risk to certain drug treatments.

Various lines of evidence suggest an association between cannabis and psychosis. Five years ago, the only significant case-control study addressing this question was the Swedish Conscript Cohort. Within the last few years, other studies have emerged, allowing the evidence for cannabis as a risk factor to be more systematically reviewed and assessed. Using specific search criteria on Embase, PsychINFO and Medline, all studies examining cannabis as an independent risk factor for schizophrenia, psychosis or psychotic symptoms, published between January 1966 and January 2004, were examined. Additional studies were also reviewed from references found in retrieved articles, reviews, and a cited reference search (ISI-Web of Science). Studies selected for meta-analysis included: (i) case-control studies where exposure to cannabis preceded the onset of schizophrenia or schizophrenia-like psychosis and (ii) cohort studies of healthy individuals recruited before the median age of illness onset, with cannabis exposure determined prospectively and blind to eventual diagnosis. Studies of psychotic symptoms were also tabulated for further discussion. Eleven studies were identified examining the relationship between cannabis use and psychosis. Seven were included in the meta-analysis, with a derived odds ratio (fixed effects) of 2·9 (95% confidence interval = 2.4-3.6). No evidence of publication bias or heterogeneity was found. Early use of cannabis did appear to increase the risk of psychosis. For psychotic symptoms, a dose-related effect of cannabis use was seen, with vulnerable groups including individuals who used cannabis during adolescence, those who had previously experienced psychotic symptoms, and those at high genetic risk of developing schizophrenia. In conclusion, the available evidence supports the hypothesis that cannabis is an independent risk factor, both for psychosis and the development of psychotic symptoms. Addressing cannabis use, particularly in vulnerable populations, is likely to have beneficial effects on psychiatric morbidity.

The recreational use of gamma hydroxy butyrate (GHB) has gained popularity over the last decade. GHB was initially sold as a safe bodybuilding and fat burning compound. It is now also widely abused by bodybuilders and young ravers. GHB attracts young people due the euphoria that it initially produces, and the claimed increase in sociability and sexual function (it is also known as liquid Ecstasy). Over the last few years, there has been an increase in the number of cases of GHB intoxication, dependence and severe withdrawal, as reported in medical literature. The situation is complicated by the use of GHB analogues, other toxic chemicals that are easily converted into GHB. GHB has recently been classified as a class ‘C’ drug in the UK, but no provisions were made in relation to GHB analogues. GHB has been increasingly used in rape cases due to its capacity to produce intoxication and amnesia. The management of patients dependent on GHB is rather complicated due to the high doses of medication that they require to control withdrawal symptoms.

The atypical antipsychotic clozapine has been reported to be associated with metabolic adverse effects, including type-2 diabetes mellitus. We present two cases of diabetes mellitus associated with clozapine treatment. One case resolved entirely upon withdrawal of the drug, whereas the other did not. We discuss the molecular basis of the diabetogenic action of clozapine and recommendations for monitoring.

We present the case of a breast-feeding woman with acute psychotic symptoms after delivery, which were treated with the antipsychotic agent risperidone. Serum levels of risperidone and 9-hydroxyrisperidone could be detected in both the mother and her infant. Drug-levels in breast milk were ten-fold lower compared to maternal serum. The patient responded well to antipsychotic treatment. Her infant did not display any adverse effects and psychomotor development was normal. In this case, risperidone was a safe treatment option for the breast-feeding mother and her infant. We also provide a brief overview of the clinically relevant data concerning antipsychotics and breast-feeding.

Lewy body disease is a common cause of dementia. Pharmacological therapies for the symptomatic treatment of this disorder are few and largely consist of acetylcholinesterase inhibitors. No guidelines exist regarding poor response or intolerability with such medications. This report discusses a case of an elderly woman with a diagnosis of probable Lewy body dementia who had significant improvement with donepezil but discontinuted it due to side effects. She was switched to rivastigmine which she tolerated and which had a similar clinical response. The process of switching is discussed in light of the lack of specific guidelines.