Journal of Psychopharmacology

Arousal is regulated by the interplay between wakefulness- and sleep-promoting nuclei. Major wakefulness-promoting nuclei are the histaminergic tuberomamillary nucleus (TMN) of the hypothalamus and the noradrenergic locus coeruleus (LC) of the pons, which also play a role in autonomic regulation. First generation antihistamines, such as diphenhydramine, are likely to cause sedation by blocking excitatory H1 histamine receptors in the cerebral cortex, and the anti-narcolepsy drug modafinil may promote wakefulness by activating the locus coeruleus. We compared the effects of single doses of diphenhydramine (75 mg) and modafinil (200 mg) on arousal and autonomic functions in 16 healthy male volunteers, using a placebo-controlled, balanced, double-blind design. Arousal was assessed by critical flicker fusion frequency (CFFF), visual analogue scales (VAS) and pupillary fatigue waves (Pupillographic Sleepiness Test (PST)). Autonomic functions measured included resting pupil diameter, light and darkness reflex responses, blood pressure, heart rate and salivation. Data were analysed with ANOVA, with multiple comparisons. Diphenhydramine had sedative effects as shown by reductions in CFFF, VAS alertness ratings and increases of the indices of pupillary fatigue. Modafinil had alerting effects as indicated by reductions in the measures of pupillary fatigue. Comparison of pre-post medication changes in pupil diameter showed a decrease after diphenhydramine and an increase after modafinil. Diphenhydramine reduced salivation, and modafinil increased systolic blood pressure. In conclusion, diphenhydramine and modafinil evoked opposite effects on arousal and sympathetic functions, which are likely to reflect their interaction with the central histaminergic and noradrenergic systems. Hyposalivation by diphenhydramine is likely to be due to its additional anticholinergic property.

The study investigated whether four specified drugs would show similar patterns on tests considered to measure sedation. In addition, their drug-effect patterns on sedation and memory performance were compared to determine whether the sedative effects could be differentiated from the memory effects.

Two double-blind, placebo-controlled, crossover studies, each with 16 healthy volunteers, were performed, one testing lorazepam (2.5 mg) and mirtazapine (15 mg) and the other olanzapine (10 mg) and haloperidol (2.5 mg). Subjective sedation was assessed by means of visual analogue scales (VAS) and objective sedation using a simple-reaction-time (SRT) task and a choice-reaction-time (CRT) task, code substitution (symbol digit substitution test (SDST)) and the peak velocity of saccadic eye movements (SEM). A verbal memory test (VMT) was administered to evaluate memory capacity.

Apart from haloperidol, all drugs proved to impair performance on all five sedation indices. Contrary to the VAS, the objective measures yielded different response profiles. Two types of drug-effect patterns emerged: one for greater impairments in response speed (SRT, SEM) and one for greater impairments in information processing (CRT, SDST). Lorazepam and olanzapine impeded memory performance, whereas mirtazapine did not. With the use of standardized scores it proved possible to differentiate between the size of the effects of the drugs on the sedation and memory tests.

To accurately assess the level and nature of sedation and to differentiate sedation from memory impairments different types of sedation measures are required. Besides studying the subjective effects, it is recommended to also test psychomotor responses and information processing speed.

This study evaLuated the cost effectiveness of oLanzapine compared with lithium as maintenance therapy for patients with bipoLar I disorder (BP1) in the UK.

A Markov model was deveLoped to assess costs and outcomes from the perspective of the UK National HeaLth Service over a 1-year period. Patients enter the modeL after stabilization of a manic episode and are then treated with olanzapine or lithium. Using the findings of a recent randomized clinical trial, the modeL considers the monthly risk of manic or depressive episodes and of dropping out from allocated therapy. Health care resources associated with acute episodes were derived primarily from a recent UK chart review. Costs of maintenance therapy and monitoring were also considered. Key factors influencing cost effectiveness were identified and included in a stochastic sensitivity analysis.

The model estimated that, compared to lithium, olanzapine significantly reduced the annual number of acute mood episodes per patient from 0.81 to 0.58 (difference —0.23; 95% CI: —0.34, —0.12). Per patient average annual care costs fell by £799 (95% CI: —£1,824, £59) driven by reduced inpatient days — but the cost difference was not statistically significant. Sensitivity analysis found the results to be robust to plausible variation in the model's parameters.

The model estimated that using olanzapine instead of lithium as maintenance therapy for BP1 would significantly reduce the rate of acute mood events resulting in reduced hospital costs. Based on available evidence, there is a high likelihood that olanzapine would reduce costs of care compared to lithium.

β3 adrenoceptor agonists show an antidepressant-like profile in preclinical rodent assays and improve mood in clinically-obese patients. These observations suggest a possible antidepressant utility for β3 adrenoceptor agonists. The present study examined the effects of acute and chronic administration of the β3 adrenoceptor agonist CL 316243 on two physiological indicators of antidepressant activity in the rat: hypothalamic 5-HT synthesis and suppression of REM sleep. 5-HT synthesis was estimated by the accumulation of 5-hydroxytryptophan (5-HTP) after treatment with the L-aromatic acid decarboxylase inhibitor NSD 1015. Sleep-wake patterns were monitored using electroencephalogram and electromyogram signals collected by radiotelemetry. Rats were administered CL 316243 acutely or once daily for 11 days. Acute administration of CL 316243 significantly increased hypothalamic 5-HT synthesis, as indicated by increased levels of 5-HTP, and reduced the amount of REM sleep. However, chronic administration produced no changes in 5-HTP or REM compared with vehicle treatment. The present observations suggest that acute administration of CL 316243 causes antidepressant-like effects on REM sleep, possibly mediated by increased central 5-HT synthesis. However, these effects are not maintained with repeated dosing.

We investigated the effects of exposure to environmental smoking-related cues (holding a lit cigarette in an environment previously associated with smoking) on cigarette craving, colour naming of smoking-related words in a modified Stroop task, and on the delay discounting of hypothetical rewards, in daily cigarette smokers (N = 30). Compared to exposure to neutral cues, exposure to smoking-related cues was associated with increased cigarette craving and slower colour naming of smoking-related compared to matched control words. However, smoking cues had no effect on delay discounting. These results suggest that smoking cues increase craving and the ability of smoking-related words to grab the attention, but do not influence impulsive decision-making. Theoretical and clinical implications are discussed.

The effects of the novel proline-containing nootropic and neuroprotective dipeptide, noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) were investigated in NMRI mice following olfactory bulbectomy. We have shown previously that these animals developed Alzheimer's disease (AD)-like behaviour, morphology and biochemistry including impairment of spatial memory, regional neuronal degeneration and elevated Aβ peptide brain levels. In the current investigation, spatial memory was assessed using the Morris water maze and serum antibodies to in vitro morphologically characterized amyloid structures of both Aβ_(25—35) peptide and equine lysozyme, as well as to neurotrophic glial factor S100b, were analyzed by enzyme-linked immunosorbent assay (ELISA). Noopept (administered at a dose of 0.01 mg/kg for a period of 21 days and during a further 5 days training) restored spatial memory and increased serum antibody levels to oligomers of Aβ_(25—35) peptide but not to equine lysozyme amyloid or S100b protein in bulbectomized animals. The positive immunotropic effect of noopept to Aβ_(25—35) peptide prefibrillar aggregates was more marked in sham-operated compared to the bulbectomized subjects which were characterized by an overall suppression of immunoreactivity. Enhancement of the immune response to Aβ_(25—35) peptide prefibrils caused by noopept may attenuate the neurotoxic consequences of amyloid fibrillization and also be associated with an improvement in spatial memory in bulbectomized mice. These actions of noopept, combined with it's previously reported neuroprotective and cholinomimetic properties, suggests that this dipeptide may well be useful for improving cognitive deficits induced by neurodegenerative diseases.

Aripiprazole, (+)terguride, OPC-4392 and (—)3-PPP have been classified as dopamine D₂ receptor partial agonists based largely on their activity in second messenger-based assays of dopamine D₂ receptor signalling. Nevertheless, signal transduction amplification might result in these compounds behaving as dopamine D₂ receptor full agonists at a more downstream level of signalling. We compared the intrinsic activity (E_max, expressed as a percentage of the maximal effect of dopamine) of aripiprazole, (+)terguride, OPC-4392 and (—)3-PPP using second (calcium (Ca²⁺) mobilization) and third (extracellular signal-regulated kinase 2 (ERK2) phosphoprotein expression) messenger readouts of cloned human dopamine D_2long (hD_2L) receptor signalling in CHO cells. These compounds were all less potent and displayed lower intrinsic activity in the Ca²⁺ assay (aripiprazole = 24.3%, (+)terguride = 56.9%, OPC-4392 = 58.6% and (—)3-PPP = 75.1%), and aripiprazole (E_max = 54.5%) displayed a substantially lower intrinsic activity than (+)terguride (E_max = 92.3%), OPC-4392 (E_max = 93.1%) and (—)3-PPP (E_max = 101.1%) in the more downstream-based ERK2 phosphoprotein expression assay. These drug effects on Ca²⁺ mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD_2L receptors, as they all were blocked by (—)raclopride, whereas (—)raclopride and other dopamine D₂ receptor antagonists (haloperidol, risperidone, ziprasidone, olanzapine, clozapine and quetiapine) were inactive on their own in both assays. These data are consistent with clinical evidence that only dopamine D₂ receptor partial agonists with a sufficiently low enough intrinsic activity will prove effective against the positive symptoms of schizophrenia, and also highlight the importance of using downstream-based assays in the discovery of novel D₂ receptor partial agonist therapeutics.

In a previous positron emission tomography (PET) study with the serotonin transporter (SERT) ligand [¹¹C](+)McN5652, we found protracted reduction of the availability of the brain SERT in users of the drug ecstasy. However, the multi-linear reference tissue method for the quantification of SERT availability used in this study is prone to effects of altered levels of statistical noise that c`ould simulate reduction of SERT. The aim of the present study was to take into account this confound by re-evaluation of the data now using a modelling approach that is rather insensitive to alterations in the level of statistical noise. A total of 116 subjects (30 current, 29 former ecstasy users, 29 drug-naive, 28 polydrug controls) in whom [ ¹¹C](+)McN5652-PET had been performed previously were re-evaluated. The equilibrium specific-to-non-specific partition coefficient V^" ₃ was obtained voxel-wise by application of the simplified reference tissue method (SRTM), which provides quite unbiased results up to rather large noise levels. Voxel-based comparisons between the groups were performed using statistical parametric mapping. V^" ₃ was reduced in the striatum and in the thalamus in current ecstasy users. This was confirmed by volume-of-interest-based analysis. This result suggests that the ecstasy-induced reduction of SERT availability in SERT-rich brain regions reported previously indicates reduced SERT binding potential rather than being an artifact of tracer kinetic modelling. SRTM analysis did not confirm previous findings in neocortical brain areas.

Stable tubule-only polypeptide (STOP) proteins are a family of microtubule associated proteins (MAPs) important in microtubule stabilization. Data indicating a role for microtubules in synaptic function has come from studies of the STOP null mouse, which exhibits synaptic deficits, in association with behavioural changes that are alleviated by antipsychotic treatment. These findings suggested that STOP mutant mice may be useful in studies of synaptic function, and could be especially relevant to schizophrenia, postulated to be a disorder of the synapse. Moreover, a genetic association between STOP and schizophrenia has been reported. This study aimed to further characterize synaptic alterations in STOP null and heterozygous mice. Using in situ hybridization histochemistry, the mRNA expression of three pre-synaptic (synaptophysin; growth associated protein-43 (GAP-43); vesicular glutamate transporter-1 (VGlut1)) and two post-synaptic (spinophilin; MAP2) proteins, was quantified in female STOP null (n = 7), heterozygous (n = 5) and wild type (n = 6) mice. For STOP null and heterozygous mice, synaptophysin, VGlut1, GAP-43 and spinophilin mRNAs were decreased in the hippocampus, whilst in addition in the null mice, synaptophysin, VGlut1 and spinophilin mRNAs were decreased in the cerebellum. Alterations in synaptic protein mRNA expression were also detected in the frontal and occipital cortex. MAP2 mRNA expression was unchanged in all brain regions. The profile of mRNA changes is broadly similar to that observed in schizophrenia. Together the data provide supporting evidence for a role for microtubules in synaptic function, and suggest that STOP, or other microtubule proteins, may contribute to the synaptic pathology of schizophrenia.

Guidelines on the prescription of benzodiazepines recommend their use be limited to the short-term relief of severe anxiety or insomnia. However, clinical experience suggests that in psychiatry these drugs may be being prescribed more widely. The aim of this survey was to investigate benzodiazepine prescribing in a specialist UK psychiatric hospital using a structured interview with consultant psychiatrists. Prescribers were also asked their views on the UK CSM guidance on benzodiazepines (1988). Of 412 inpatients, 77 (18.7%) were receiving 90 benzodiazepine prescriptions for psychiatric indications. Most prescriptions were for anxiety (45/90; 50.0%), aggression (23/90; 25.6%) and agitation (13/90; 14.4%). Use was commonest for acquired brain injury, schizophrenia and personality disorders. Much usage was chronic (only 4/90 (4.4%) prescriptions had been initiated within the previous 4 weeks) and off-label (85/90; 94.4%). Prescribers were concerned about the addictive nature of benzodiazepines for these patients and to a lesser extent about their abuse potential. Most consultants believed the UK CSM guidance was too restrictive in relation to their clinical practice and needed modification to encompass new indications, for example rapid tranquillization, and specialist prescribing. In psychiatry benzodiazepines are quite frequently used in the management of a number of groups of difficult to treat patients. Although largely not evidence based, some psychiatrists report a favourable risk—benefit ratio for benzodiazepines in the treatment of certain patients.

Prediction of the response to different classes of antidepressants has been an important matter of concern in the field of psychopharmacology. The purpose of the present study was to investigate whether the G196A polymorphism of the brain-derived neurotrophic factor (BDNF) gene is associated with the antidepressant effect of milnacipran, a serotonin norepinephrine reuptake inhibitor, and fluvoxamine, a selective serotonin reuptake inhibitor. The subjects of our previous study of milnacipran (n = 80) and fluvoxamine (n = 54) were included in the present study. Severity of depression was assessed with the Montgomery Åsberg depression rating scale (MADRS). Assessments were carried out at baseline and at 1, 2, 4 and 6 weeks of treatment. Polymerase chain reaction was used to determine allelic variants. In all subjects receiving milnacipran or fluvoxamine, the G/A genotype of the BDNF G196A polymorphism was associated with a significantly better therapeutic effect in the MADRS scores during this study. When milnacipran and fluvoxamine-treated subjects were analysed independently, the G/A genotype group showed greater reduction of MADRS scores than other genotype groups, irrespective of which antidepressant was administered. These results suggest that the BDNF G196A polymorphism in part determines the antidepressant effect of both milnacipran and fluvoxamine.

Use of combined antipsychotics for patients with treatmentresistant/refractory schizophrenia is common practice in psychiatry. The objective of this paper is to review the current literature on combining non-clozapine atypical antipsychotics as well as discussing the theoretical benefits and risks, and summarizing the implications for clinical practice.

We found in cases of treatment-resistant schizophrenia, where clozapine is deemed inappropriate, combination therapy with non-clozapine atypical antipsychotics is a strategy worthy of consideration. Combinations using olanzapine with either amisulpride or risperidone — or quetiapine with risperidone — in theory act on different receptor profiles and in the limited data available have shown improvement in symptoms, been used most frequently, and on balance have more data on safety. Initial case reports suggest that aripiprazole combined with non-clozapine atypicals may worsen psychosis.

The current literature, however, has significant limitations. For this reason, due to the lack of data on safety, caution is recommended. There needs to be further well-designed studies with the aim to specifically investigate the effects of combination therapy to allow the clinician to better balance the risks and benefits (both clinical and economical) of treatment.

Hyponatraemia is a very rare but potentially fatal complication of SSRIs and citalopram therapy, especially during the first weeks of treatment and for those who concomitantly use medications known to cause hyponatraemia. We present a 54-year-old hypertensive female patient who was admitted to the hospital with drowsiness, paresthesia, fatigue, nausea, vomiting and visual hallucinations and who was diagnosed to have syndrome of inappropriate secretion of antidiuretic hormone (SIADH) due to citalopram. All her presenting symptoms disappeared after discontinuation of citalopram therapy, fluid restriction and a careful hypertonic saline infusion. This case suggests that SIADH may develop among hypertensive patients, especially when they use diuretics or follow a salt restricted diet.