Depression: Goadsby PJ

Goadsby PJ. · No affiliation provided · J Neurophysiol. · Pubmed #17409171 links to  free full text

This publication has no abstract.

Goadsby PJ. · No affiliation provided · Ann Neurol. · Pubmed #11198295 No free full text.

This publication has no abstract.

Bigal ME, Lipton RB, Holland PR, Goadsby PJ. · Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. · Neurology. · Pubmed #17515549 No free full text.

Abstract: Migraine and obesity are associated in several ways. First, both are prevalent and disabling disorders influenced by genetic and environmental risk factors. Second, migraine with aura, as obesity, seems to be a risk factor for cardiovascular events. Finally, large population-based studies suggest that obesity is a risk factor for chronic migraine after adjusting for comorbidities. In this article, we discuss plausible mechanisms that may account for this association. Several of the inflammatory mediators that are increased in obese individuals are important in migraine pathophysiology, including interleukins and calcitonin gene-related peptide (CGRP). These mediators may increase the frequency, severity, and duration of migraine attacks per se, which in turn would cause central sensitization. Repeated central sensitization may be associated with permanent neuronal damage close to the periaqueductal gray area, with poor modulation to pain. Obesity is also a state of sympathetic activation, which may contribute to increase in headache frequency. Furthermore, the levels of adiponectin are decreased in obesity. At low but not normal levels, adiponectin is nociceptive. Shared biologic predisposition may also play a major role. Orexins modulate both pain and metabolism. Dysfunction in the orexins pathways seems to be a risk factor for both conditions. Finally, conditions that are comorbid to both states (e.g., depression, sleep apnea) may also make the relationship between both diseases more complex.

Goadsby PJ. · Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. · Trends Mol Med. · Pubmed #17141570 No free full text.

Abstract: Migraine is a complex, disabling disorder of the brain that manifests itself as attacks of often severe, throbbing head pain with sensory sensitivity to light, sound and head movement. There is a clear familial tendency to migraine, which has been well defined in a rare autosomal dominant form of familial hemiplegic migraine (FHM). FHM mutations so far identified include those in CACNA1A (P/Q voltage-gated Ca(2+) channel), ATP1A2 (N(+)-K(+)-ATPase) and SCN1A (Na(+) channel) genes. Physiological studies in humans and studies of the experimental correlate--cortical spreading depression (CSD)--provide understanding of aura, and have explored in recent years the effect of migraine preventives in CSD. Therapeutic developments in migraine have come by targeting the trigeminovascular system, with the most-recent being the proof-of-principle study of calcitonin gene-related peptide (CGRP) receptor antagonists in acute migraine. To understand the basic pathophysiology of migraine, brain imaging studies have firmly established reproducible changes in the brainstem in regions that include areas that are involved in sensory modulation. These data lead to the view that migraine is a form of sensory dysmodulatio--a system failure of normal sensory processing.

Andreou AP, Goadsby PJ. · Headache Group, Department of Neurology, University of California-San Francisco, 1635 Divisadero St, San Francisco, CA 94115, USA · Expert Opin Investig Drugs. · Pubmed #19426123 No free full text.

Abstract: BACKGROUND: Migraine is a common and disabling neurological disorder. Although the pharmacotherapy of migraine has advanced in parallel with our understanding of the pathophysiology of the disease, there is still a considerable unmet need to find more effective treatments. Migraine pathophysiology involves activation or the perception of activation of the trigeminovascular system. Glutamate, the major excitatory neurotransmitter in the CNS, is implicated in elements of the pathophysiology of the disorder, including trigeminovascular activation, central sensitization and cortical spreading depression. OBJECTIVE: The aim of this article is to review the potential use of glutamate receptor antagonists as innovative neuronally targeted treatments of migraine. METHODS: A systematic search of peer-reviewed publications was performed in PubMed on glutamate and migraine/trigeminovascular activation, and important references providing an insight into migraine pathophysiology are included. The results of unpublished trials were obtained from presentations at national and international meetings. RESULTS/CONCLUSIONS: The preclinical and clinical data argue strongly for a role of glutamatergic receptor activation in migraine. The pharmacology of glutamatergic trigeminovascular responses in brain areas involved in migraine pathophysiology is relevant to the development of new therapies for this disabling condition. Glutamate receptors represent a promising target for a valuable, non-vasoconstrictor, and perhaps more importantly neuronal-specific therapeutic approach to the treatment of migraine.

Goadsby PJ, Ferrari MD, Csanyi A, Olesen J, Mills JG, Anonymous00179. · Headache Group, Institute of Neurology, London, UK. · Cephalalgia. · Pubmed #19222510 No free full text.

Abstract: Tonabersat is a novel putative migraine prophylactic agent with an unique stereospecific binding site in the brain. Tonabersat has been shown, in animal models, to inhibit experimentally induced cortical spreading depression, the likely underlying mechanism for migraine aura, and cerebrovascular responses to trigeminal nerve stimulation. The aim was to study the potential for tonabersat as a migraine preventive. A randomized, double-blind, placebo-controlled, multicentre, parallel group study recruited patients with migraine with and without aura experiencing between two and six migraine attacks per month. After a 1-month baseline they received tonabersat 20 mg daily for 2 weeks and 40 mg daily for a further 10 weeks. The primary end-point was the change in mean number of migraine headache days between the third month and the baseline period in the intention-to-treat population comparing the placebo (n = 65) and tonabersat (n = 58) groups. At the primary end-point there was a 1.0-day (95% confidence interval -0.33, 2.39; P = 0.14) difference in reduction in migraine days between tonabersat and placebo. There were 10 secondary efficacy end-points, of which two were statistically significant. In month 3 of treatment, the responder rate, defined as a 50% reduction in migraine attacks, was 62% for tonabersat and 45% for placebo (P < 0.05), and the rescue medication use was reduced in the tonabersat group compared with placebo by 1.8 days (P = 0.02). Placebo responses were particularly high for all end-points. At least one treatment-emergent adverse event was reported in the tonabersat group in 61% of patients compared with 51% in the placebo group; none was worrisome. Placebo responses were unexpectedly high in this trial, complicating straightforward interpretation of the study results. The good tolerability and promising efficacy results support further exploration of higher doses of tonabersat in larger controlled trials.

Akerman S, Holland PR, Goadsby PJ. · Department of Neurology, University of California, San Francisco, 505 Parnassus Avenue, San Francisco CA 94143-0114, USA. · Brain Res. · Pubmed #18656463 No free full text.

Abstract: Migraine with aura occurs in up to 20-30% of all migraineurs. The regional cerebral blood flow (rCBF) changes that occur during cortical spreading depression (CSD) are considered to be an experimental correlate of aura. CSD is synchronous with a failure in brain ion homeostasis and efflux of excitatory amino acids from nerve cells. Therefore studying the mechanisms that underlie CSD, such as ion channel manipulation, and observing rCBF changes may help our understanding of migraine aura. In this study we used mechanical stimulation to induce oligemia and hyperemia, in surgically prepared cats and rats, using laser Doppler probes to measure the cerebral blood flow and single cell cortical recording to measure the spike/neuronal burst, both generated as a consequence of CSD. We looked at the response of ion channel blockers directed at sodium, voltage-dependent calcium and ATP-activated potassium ion channels. The sodium ion channel blocker was able to inhibit rCBF changes in both the cat and rats. Voltage-dependent calcium channel blockers had little effect on the initiation or propagation of the spread, as did the ATP-activated potassium channel blocker. The data are consistent with what is known of human aura in that sodium ion channels are those predominantly involved in mechanical stimulation-induced rCBF changes and thus may represent therapeutic targets for the aura response in migraine.

Akerman S, Goadsby PJ. · Headache Group, Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. · Neuroreport. · Pubmed #16056144 No free full text.

Abstract: Cortical spreading depression is thought to be the pathophysiological correlate of the neurological symptoms in migraine with aura. Topiramate is an anti-epileptic drug that is also used as a migraine preventive. Ion homeostasis and excitatory amino acid efflux are major components of cortical spreading depression; so given the broad range of actions of topiramate, we examined its effect on cortical spreading depression. Cortical spreading depression was elicited by a needle stick in the cortex in surgically prepared rats and cats; laser Doppler probes were used to measure the cerebral blood flow and a recording electrode was used to measure electrical nerve cell activity. Topiramate at 30 mg kg(-1) was able to inhibit regional cerebral blood flow changes and cortical depolarization and spreading depression in all rats, and in 8 of 13 cats. We conclude that topiramate may act on mechanisms involved in the initiation and propagation of spreading depression, and that these mechanisms may be similar to those involved in the therapeutic role.

Mitsikostas DD, Sfikakis PP, Goadsby PJ. · Athens Naval Hospital, Department of Neurology, Headache Clinic, Athens, Greece. · Brain. · Pubmed #15047589 links to  free full text

Abstract: Controversies in the occurrence and implications of headache in patients suffering from systemic lupus erythematosus (SLE) triggered us to conduct an extensive literature search in order to answer five clinical questions. (i) Is headache prevalence higher in SLE patients than in the general population? (ii) Is 'lupus headache' a separate entity? (iii) Is there a distinct pathogenetic mechanism of headache in SLE? (iv) Is headache related to CNS involvement or general SLE activity? (v) Is headache related to anxiety- and depression-like symptoms in SLE? All published articles reporting data from >30 SLE patients were classified into four classes (I, IIa, IIb and III) by the quality of their evidence. We found no prospective controlled study (class I), but we identified seven controlled (class II) and 28 uncontrolled studies (class III) that retrospectively investigated the occurrence of headache in SLE patients. Eight out of 35 studies applied the International Headache Society (IHS) criteria for headache classification, whereas only four uncontrolled studies investigated paediatric SLE populations (class III). Pooled data from eight studies (controlled and uncontrolled) that used the IHS criteria show that 57.1% of SLE patients reported any type of headache (migraine 31.7% and tension-type headache 23.5%). Pooled data from seven controlled studies showed that the prevalence of all headache types, including migraine, was not different from controls. Insufficient evidence was found for the concept of 'lupus headache'. No particular pathogenetic mechanism of headache in adult SLE patients has been identified, nor an association between headache and the disease status, including CNS involvement. There is no good evidence that headache is associated with anxiety and depression in SLE. Insufficient data (class III) do not allow safe conclusions for headache among paediatric SLE patients. These findings suggest that the occurrence of headache in adult SLE patients does not itself require further investigation and that headache in those patients should be classified according to IHS criteria and managed as primary headache if there is no specific indication of a role for SLE in the patient. These recommendations should be verified by a properly controlled and prospective study in both adult and paediatric populations.

Akerman S, Kaube H, Goadsby PJ. · Headache Group, Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. · J Pharmacol Exp Ther. · Pubmed #14718591 links to  free full text

Abstract: Arachidonylethanolamide (anandamide, AEA) is believed to be the endogenous ligand of the cannabinoid CB(1) and CB(2) receptors. CB(1) receptors have been found localized on fibers in the spinal trigeminal tract and spinal trigeminal nucleus caudalis. Known behavioral effects of anandamide are antinociception, catalepsy, hypothermia, and depression of motor activity, similar to Delta(9)-tetrahydocannanbinol, the psychoactive constituent of cannabis. It may be a possible therapeutic target for migraine. In this study, we looked at the possible role of the CB(1) receptor in the trigeminovascular system, using intravital microscopy to study the effects of anandamide against various vasodilator agents. Anandamide was able to inhibit dural blood vessel dilation brought about by electrical stimulation by 50%, calcitonin gene-related peptide (CGRP) by 30%, capsaicin by 45%, and nitric oxide by 40%. CGRP(8-37) was also able to attenuate nitric oxide (NO)-induced dilation by 50%. The anandamide inhibition was reversed by the CB(1) receptor antagonist AM251. Anandamide also reduced the blood pressure changes caused by CGRP injection, this effect was not reversed by AM251. It would seem that anandamide acts both presynaptically, to prevent CGRP release from trigeminal sensory fibers, and postsynaptically to inhibit the CGRP-induced NO release in the smooth muscle of dural arteries. CB(1) receptors seem to be involved in the NO/CGRP relationship that exists in causing headache and dural blood vessel dilation. It also seems that some of the blood pressure changes caused by anandamide are mediated by a noncannabinoid receptor, as AM251 was unable to reverse these effects. It can be suggested that anandamide is tonically released to play some form of modulatory role in the trigeminovascular system.

Millson D, Frischer M, Croft P, Goadsby PJ. · Primary Care Sciences Research Centre, Keele University, London, UK. · Cephalalgia. · Pubmed #11167903 No free full text.

Abstract: 1997, sumatriptan-treated migraineurs had significantly higher depression PCRs (22.3%) compared with non-triptan users (19.3%), a difference of 6.4% (95% confidence interval (CI) 4.6-8.4%, P < 0.001). In the year (April 1997 to March 1998) following the launch of the TELs, depression PCRs were significantly higher among patients using these compounds compared with sumatriptan-treated patients (5.1%, CI 1.8-12.0%, P < 0.05). However, after taking account of prior depression (odds ratio (OR) 6.45, 95% CI 3.63-11.43), TELs were not significantly associated with depression (OR 0.27, 95% CI 0.03-2.13). Furthermore, rates of newly diagnosed depression after treatment were similar in the two triptan groups (sumatriptan 4.2%; TELs 3.9%). Although, the TELs are being prescribed to patients with higher pre-existing rates of depression, they are not associated with subsequently increased consulting for depressive illness compared with patients taking sumatriptan. This study highlights the potential to use GPRD to test targeted hypotheses exploring pharmacovigilance issues for patients using new medicines.

Kaube H, Knight YE, Storer RJ, Hoskin KL, May A, Goadsby PJ. · Department of Neurology, University of Essen, Germany. · Cephalalgia. · Pubmed #10448547 No free full text.

Abstract: It remains an open question as to whether cortical spreading depression (CSD) is the pathophysiological correlate of the neurological symptoms in migraine with aura. In the experimental animal, CSD is an electrophysiological phenomenon mainly mediated via NMDA receptors. However, according to case reports in humans, visual aura in migraine can be alleviated by vasodilator substances, such as amyl nitrite and isoprenaline. There is also circumstantial evidence that brainstem nuclei (dorsal raphe nucleus and locus coeruleus) may play a pivotal role in the initiation of aura. In this study, CSD was elicited in alpha-chloralose anesthetized cats by cortical needle stab injury and monitored by means of laser Doppler flowmetry. Topical application of isoprenaline (0.1-1%) and amyl nitrite (0.05%) onto the exposed cortex had no effect on the elicitation or propagation of CSD. Also, after supracollicular transection, subsequent CSDs showed no differences in the speed of propagation and associated flow changes. We conclude from these data that--given CSD probably exists in humans during migraine--spreading neurological deficits during migraine aura are independent of brainstem influence and have a primarily neuronal rather than vascular mechanism of generation.

Cittadini E, Goadsby PJ. · Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #15965225 links to  free full text

Abstract: A patient is reported with psychological change characterised by impaired concentration and thought projection, followed by both severe anxiety and depression, starting after three weeks on high dose methysergide. The acute problem settled slowly after methysergide withdrawal and is likely to represent an unusual and serious side effect of that drug.