British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders.

Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.

Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.

Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma-secretase inhibitors will enable a clinical examination of the A beta hypothesis that Ass peptide drives the neuropathology observed in Alzheimer's disease.

Transient ischaemic attacks: evaluation and management.

Transient ischaemic attacks (TIAs) are temporary focal cerebral or retinal deficits that resolve within 24 hours. Attention should be given to the tempo and localisation of the clinical syndrome, as multiple and hemispheric TIAs are associated with the greatest incidence of early stroke. Evaluation of TIAs depends on the clinical symptoms, physical examination and investigations. Attention should be given to clinical evidence of generalised atherosclerotic disease, as death due to the complications of ischaemic heart disease is the commonest outcome in patients with TIA. Early attention should focus on risk factor modification, with emphasis on the treatment of hypertension and smoking cessation. Antiplatelet therapy should be instituted. Aspirin is the first-line treatment but, if not tolerated, clopidogrel is effective in preventing vascular complications. Anticoagulants are generally reserved for patients with atrial fibrillation and are associated with a significant reduction of stroke risk. The use of statins is becoming more widespread, with emerging evidence of their efficacy in reducing stroke risk. The risk of stroke is greatest in the weeks following TIA and patients should be referred for carotid duplex ultrasonography. Carotid endarterectomy for symptomatic internal carotid artery high grade stenosis virtually abolishes stroke risk in that vascular territory over subsequent years. TIAs should be regarded as an emergency requiring early diagnosis and prompt referral.

The timing of primary orthostatic tremor bursts has a task-specific plasticity.

Primary orthostatic tremor is characterized by unsteadiness and shakiness of the legs while standing. It is due to a remarkably strong and regular EMG modulation at approximately 16 Hz that is thought to be of CNS origin. Previous studies have shown that the tremor frequency is the same in all involved muscles and that the time relation between bursts of activity in different muscles may be fixed (e.g. always co-contracting or always contracting in an alternating pattern). Here we have used frequency domain analysis of postural muscle EMG signals in five primary orthostatic tremor patients and in two normal controls to explore the nature of such fixed timing patterns. The timing is found not to relate simply to the relative conduction times for passage of rhythmic bursts from a central oscillation to different muscles. Indeed, although the timing pattern (expressed as phase) of the 16-Hz EMG bursts in different postural muscles remains constant while the subject adopts a certain steady posture, it is different for different subjects and also changes when the same subject adopts a different posture. It seems unlikely that such complex task-dependent timing relations of rhythmic postural muscle activity are due to the primary pathology of primary orthostatic tremor. Instead, we suggest that the abnormally strong peripheral manifestation of a 16-Hz CNS oscillation merely unmasks normal central processes so that the timing patterns may provide a clue to the nature of postural motor control.

Structure-activity relationship of a series of diaminoalkyl substituted benzimidazole as neuropeptide Y Y1 receptor antagonists.

A series of benzimidazoles (4) was synthesized and evaluated in vitro as potent and selective NPY Y1 receptor antagonists. Substitution of the piperidine nitrogen of 4 with appropriate R groups resulted in compounds with more than 80-fold higher affinity at the Y receptor compared to the parent compound 5 (R = H). The most potent benzimidazole in this series was 21 (Ki = 0.052 nM).

Structure-activity relationships of a series of benzothiophene-derived NPY Y1 antagonists: optimization of the C-2 side chain.

A series of benzo[b]thiophene-derived NPY-1 receptor antagonists is described. Systematic modification of the C-2 substituent afforded a 1000-fold range in Y1 receptor affinity. Appropriate substitution at the ortho and para positions of the C-2 phenyl ether produced a synergistic effect on Y1 binding affinity, which led to the discovery of the most active ligands, 12t (K(i) = 15 nM), 12u (K(i) = 11 nM), and 12v (K(i) = 13 nM).

Synthesis and evaluation of a series of novel 2-[(4-chlorophenoxy)methyl]benzimidazoles as selective neuropeptide Y Y1 receptor antagonists.

A series of novel benzimidazoles (BI) derived from the indole 2 was synthesized and evaluated as selective neuropeptide Y (NPY) Y1 receptor antagonists with the aim of developing antiobesity drugs. In our SAR approach, the (4-chlorophenoxy)methyl group at C-2 was kept constant and a series of BIs substituted with various piperidinylalkyl groups at N-1 was synthesized to identify the optimal spacing and orientation of the piperidine ring nitrogen relative to the benzimidazole. The 3-(3-piperidinyl)propyl in 33 was found to maximize affinity for the Y1 receptor. Because of the critical importance of Arg33 and Arg35 of NPY binding to the Y1 receptor, the incorporation of an additional aminoalkyl functionality to the structure of 33 was explored. Methyl substitution was used to probe where substitution on the aromatic ring was best tolerated. In this fashion, the C-4 was chosen for the substitution of the second aminoalkyl functionality. Synthesis of such compounds with a phenoxy tether using the 4-hydroxybenzimidazole 11 was pursued because of their relative ease of synthesis. Functionalization of the hydroxy group of 45 with a series of piperidinylalkyl groups provided the dibasic benzimidazoles 55-62. Among them, BI 56 demonstrated a Ki of 0.0017 microM, which was 400-fold more potent than 33. To evaluate if there was a stereoselective effect on affinity for these BIs, the four constituent stereoisomers (69-72) of the BI 60 were prepared using the S- and R-isomers of bromide 17. Antagonist activity of these BIs was confirmed by measuring the ability of selected compounds to reverse NPY-induced forskolin-stimulated cyclic AMP. The high selectivity of several BI antagonists for the Y1 versus Y2, Y4, and Y5 receptors was also shown.

Structure-activity relationships of a series of 1-substituted-4-methylbenzimidazole neuropeptide Y-1 receptor antagonists.

The characterization of a novel series of NPY-1 receptor antagonists derived from the 4-methylbenzimidazole 4 is described. Appropriate substitution on the piperidyl nitrogen of 4 led to systematic increases in Y-1 receptor affinity, to approximately 50-fold, and to the discovery of the importance of a second basic substituent.

Tremor associated with benign IgM paraproteinaemic neuropathy.

The clinical and neurophysiological features of six patients with action tremor of the upper limbs associated with IgM paraproteinaemic neuropathy are described. Symptomatic tremor was confined to the upper limbs and was broadly symmetrical. The frequency of associated rhythmic muscle activity ranged from 2.8 to 5.5 Hz in abductor pollicis brevis and from 3.7 to 5.5 Hz in the forearm flexor muscles. Magnetic brain stimulation, somatosensory evoked potentials (SEPs) and stretch reflex studies did not provide evidence for delayed conduction within central pathways. There was marked slowing of the maximum motor conduction velocities in peripheral nerves. Forearm stretch reflexes were present but their latencies were prolonged. Somatosensory evoked potentials were obtained in the majority of patients, but were delayed. Wrist tremor could be modulated by mechanical perturbations or median nerve electrical shocks. Simple voluntary wrist movements were of normal duration and peak velocity, but the kinematic profile was asymmetric. Each movement was associated with a triphasic EMG pattern in agonist-antagonist-agonist muscles but the durations of the bursts were prolonged and the onset of the second agonist was delayed. These results support the hypothesis that distorted, mistimed peripheral inputs reach a central processor (probably the cerebellum) which although intact is misled into producing tremor in certain parts of the body.

Primary writing tremor.

Primary writing tremor (PWT) is considered to be a type of task-specific tremor in which tremor predominantly occurs and interferes with handwriting. We describe the clinical and neurophysiological features of 21 patients (20 male and one female) with PWT. Mean age at tremor onset was 50.1 years. A family history of PWT was obtained from seven patients. Ten patients obtained benefit from drug treatment (mainly propranalol or primidone) and seven responded to alcohol. The writing speeds of the patients (mean +/- SEM: 73.1 +/- 6.6 letters per minute) when using their preferred hand were significantly reduced (Student's t test: P < 0.001) compared with those of healthy control subjects (mean +/- SEM: 127.7 +/- 6.4). Surface polymyography performed during writing showed 4.1-7.3 Hz rhythmic activity predominantly in the intrinsic hand and forearm muscles. Alternating, extensor activation alone, skipping from alternating to extensor activation, and co-contracting EMG patterns were recorded from the flexor and extensor muscles of the forearm. There was no evidence for excessive 'overflow' of this rhythmic EMG activity, as similar activity was detected in comparable muscle groups of healthy control subjects. Accelerometry confirmed that the frequency of PWT ranged from 4.1-7.3 Hz (median 5.5 Hz) and that normal subjects wrote with a 4.0-7.7 Hz oscillation (median 4.6 Hz). Forearm reciprocal inhibition was normal in PWT (n = 13), and thus patients with PWT can be distinguished from those with writer's cramp in whom decreased presynaptic inhibition has been found. Patients were sub-classified as having either type A (n = 11) or B (n = 10) PWT depending on whether tremor appeared during writing (type A: task induced tremor) or whilst writing and adopting the hand position used in writing (type B: positionally sensitive tremor). However, the only differences between these two groups were that a co-contracting EMG pattern and tremor induced by tendon taps to the volar aspect of the wrist were present in type B but not type A cases.

Essential tremor and its variants.

Essential tremor is the commonest of movement disorders. Although sometimes prefaced with the term 'benign', it often causes significant disability. Diagnosis is based on the clinical finding of a postural tremor, predominantly affecting the upper limbs, that is absent at rest and not associated with extrapyramidal or cerebellar signs. There are, as yet, no specific anatomical, physiological, biochemical or genetic markers for the condition. Postural limb tremors, clinically indistinguishable from essential tremor, may occur in patients who have, or will later develop, other neurological conditions; whether such patients have essential tremor is a matter of controversy that will only be resolved with a better understanding of the pathophysiology of essential tremor. Positron emission tomography in patients with essential tremor reveals increased cerebellar activity even at rest, a finding that is consistent with the cerebellum having an important role in the generation of tremor. Abnormal cerebellar function has also been invoked to account for the abnormal manner in which patients with essential tremor perform rapid voluntary wrist movements. Molecular genetic studies in hereditary essential tremor have been initiated, but with negative results so far. Several new drug treatments have been tried, but with limited success; the role of thalamic stimulation and botulinum toxin in the treatment of essential tremor remains to be judged.