Cannabinoids: Emerging developments in neuropsychopharmacology and biological psychiatry.

Cannabinoids from the cannabis plant were one of the earliest psychoactive phytochemicals harnessed by humanity for their medicinal properties and remain one of the most frequently used and misused classes of chemicals in the world. Despite our long-standing history with cannabinoids, much more is said than is known regarding how these molecules influence the brain and behavior. We are in a rapidly evolving discovery phase regarding the neuroscience of cannabinoids. This period of insight began in the mid-1990s when it was discovered that phytocannabinoids (e.g., delta-9-tetrahydrocannabinol) act on G protein-coupled receptors (i.e., CB1/CB2) in the brain to produce their psychoactive effects. Shortly thereafter, it was discovered that endogenous ligands (i.e., endocannabinoids) exist for these receptor targets and, that they are synthetized on demand under a variety of physiological conditions. Thus, we can now study how phytochemicals, endogenous ligands, and synthetic/metabolic enzymes of the endocannabinoid system influence the brain and behavior by activating known receptor targets. Our increased ability to study cannabinoid interactions with the brain and behavior coincides with an increase in international interest in utilizing cannabinoids as a medicine. At the same time, the potency of, and administration routes by which cannabinoids are used is rapidly changing. And, these trends in cannabinoid misuse are producing lasting neural adaptations that have implications for mental health. In this special edition, we will summarize our recent period of discovery regarding how: 1) phytocannabinoids, synthetic cannabinoids and endocannabinoids act on the brain to produce behavioral effects; 2) cannabinoids can be harnessed to produce pharmacotherapeutic utility in the field of medicine; and 3) use of increasingly more cannabinoid variants through unique routes of administration alter the brain and behavior, especially when used in critical developmental periods like pregnancy and adolescence.

Efectos de los inductores antiepilépticos en la neuropsicofarmacología: una cuestión ignorada. Parte II: cuestiones farmacológicas y comprensión adicional / The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part II: pharmacological issues and further understanding

La literatura sobre los inductores en la epilepsia y el trastorno bipolar está contaminada por falsos negativos. Esta segunda parte de una revisión exhaustiva sobre los fármacos antiepilépticos (FAE) con propiedades inductoras aporta más material educativo a los clínicos acerca de la complejidad de interpretar sus interacciones farmacológicas. Se revisa la farmacología básica de la inducción incluyendo los citocromos P450 (CYP), las enzimas de glucuronización (UGT) y la glucoproteína P (P-gp). Los CYP2B6 y CYP3A4 son muy sensibles a la inducción. El CYP1A2 es moderadamente sensible. Los el CYP2C9 y el CYP2C19 son solo levemente sensibles. El CYP2D6 no puede ser inducida por los fármacos. La inducción de las enzimas metabólicas, los CYP o las UGT, y los transportadores como la P-gp, se debe a un incremento de la síntesis de estas proteínas mediado por los denominados receptores nucleares (receptores constitutivo de androstano, de los estrógenos, de los glucocorticoides y de pregnano X). Aunque la primera parte de este artículo describe los factores de corrección para los antiepilépticos inductores, la extrapolación de estos valores desde un paciente promedio a un individuo concreto está influenciada por la ruta de administración, la carencia de la enzima metabólica debida a razones genéticas, y la presencia de inhibidores, u otros inductores. También pueden ser importantes las interacciones farmacológicas de los FAE al nivel de los mecanismos farmacodinámicos. Se describen 6 pacientes con una sensibilidad extrema a los inductores antiepilépticos (AU)

The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. Part II of this comprehensive review on antiepileptic drug (AED) inducers provides clinicians with further educational material about the complexity of interpreting AED drug-drug interactions. The basic pharmacology of induction is reviewed including the cytochrome P450 (CYP) isoenzymes, the Uridine Diphosphate Glucuronosyltransferases (UGTs), and P-glycoprotein (P-gp). CYP2B6 and CYP3A4 are very sensitive to induction. CYP1A2 is moderately sensitive while CYP2C9 and CYP2C19 are only mildly sensitive. CYP2D6 cannot be induced by medications. Induction of UGT and P-gp are poorly understood. The induction of metabolic enzymes such as CYPs and UGTs, and transporters such as P-gp, implies that the amount of these proteins increases when they are induced; this is almost always explained by increasing synthesis mediated by the so-called nuclear receptors (constitutive androstane, estrogen, glucocorticoid receptors and pregnane X receptors). Although part i provides correction factors for AEDs, extrapolation from an average to an individual patient may be influenced by administration route, absence of metabolic enzyme for genetic reasons, and presence of inhibitors or other inducers. AED pharmacodynamic DDIs may also be important. Six patients with extreme sensitivity to AED inductive effects are described (AU)

Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior.

The potential contribution of chronic inflammation to the development of neuropsychiatric disorders such as major depression has received increasing attention. Elevated biomarkers of inflammation, including inflammatory cytokines and acute-phase proteins, have been found in depressed patients, and administration of inflammatory stimuli has been associated with the development of depressive symptoms. Data also have demonstrated that inflammatory cytokines can interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits relevant to mood regulation. Further understanding of mechanisms by which cytokines alter behavior have revealed a host of pharmacologic targets that may be unique to the impact of inflammation on behavior and may be especially relevant to the treatment and prevention of depression in patients with evidence of increased inflammation. Such targets include the inflammatory signaling pathways cyclooxygenase, p38 mitogen-activated protein kinase, and nuclear factor-κB, as well as the metabolic enzyme, indoleamine-2,3-dioxygenase, which breaks down tryptophan into kynurenine. Other targets include the cytokines themselves in addition to chemokines, which attract inflammatory cells from the periphery to the brain. Psychosocial stress, diet, obesity, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells also contribute to inflammation and may serve as a focus for preventative strategies relevant to both the development of depression and its recurrence. Taken together, identification of mechanisms by which cytokines influence behavior may reveal a panoply of personalized treatment options that target the unique contributions of the immune system to depression.

Farmacoterapia para niños con síndrome de Down / No disponible

El campo de la farmacología cognitiva para niños con discapacidad intelectual no existe todavía, pero el reciente desarrollo de la investigación que atiende a este objetivo parece prometedor. La investigación informada por la neurociencia, dirigida a conocer la base neurobiológica de la discapacidad intelectual en el síndrome de Down y otras patologías neurogenéticas está empezando a acumular una masa crítica investigadora con la atracción necesaria para avanzar hacia adelante. Agentes farmacológicos que apuntan a receptores GABA y glutamato y transportadores de dopamina ofrecen perspectivas como para iniciar ensayos clínicos. Las terapias basadas en células e intervenciones biológicas relacionadas con ellas se encuentran todavía en etapas muy inmaduras o ensayo preclínico, pero la infraestructura y los recursos que se necesitan para apoyar estos esfuerzos investigadores están lejos de conseguirse, lo que dificulta el progreso en este campo. La capacidad para convertir hallazgos fundamentales conseguidos desde la neurofarmacología y la neurociencia cognitiva en terapias fundamentadas en dichos hallazgos que mejoren las vidas de los niños con trisomía 21 sigue siendo, pues, todo un reto digno de afrontar (AU)

No disponible

New therapeutic developments in chronic migraine.

PURPOSE OF REVIEW: Chronic migraine is a common cause of chronic daily headache, which is often refractory to standard treatment. New research has increased our understanding of this disorder and its treatment. This review focuses on recent clinical trials and advances in our understanding of migraine pathophysiology. RECENT FINDINGS: Migraine research has traditionally focused on the more common episodic form of the disorder, but recent clinical trials have started to focus on chronic migraine or chronic daily headache. Topiramate, onabotulinum toxin type A, gabapentin, petasites and tizanidine are among the agents that appear to be effective in the treatment of chronic migraine. New acute medications including an inhaled form of dihydroergotamine will soon be available and neuromodulatory procedures such as occipital nerve stimulation may be effective for the most disabled patients. In the past few years, other studies have shed light on potential risk factors for chronic migraine such as medication-overuse headache, temporomandibular disorders, obstructive sleep apnea and obesity. SUMMARY: This review explains advances in the treatment of chronic migraine, a common disorder seen in neurological practice. These new advances in preventive treatment and a better understanding of its risk factors will allow clinicians to better identify individuals at greatest risk and prevent the development of chronic migraine.

14th International Headache Congress: clinical highlights.

The 14th International Headache Congress was held in Philadelphia in September 2009. During the Congress, many important basic, translational, and patient-oriented research studies were presented. In this and an accompanying manuscript, the work that has been deemed to be among the most innovative and significant is summarized. This manuscript discusses the best clinical research, while the accompanying manuscript summarizes the top basic science research. Here, we provide background and summarize Congress presentations on novel agents for migraine treatment, botulinum toxin therapy for chronic migraine, new methods for administration of headache medications, and nerve stimulation for the treatment of medically refractory headaches.

Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.

The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials. Clinical trial results of TRPV1 agonists such as resiniferatoxin in interstitial cystitis, NGX 4010 in post-herpetic neuralgia, and 4975 (Adlea) in osteoarthritis, bunionectomy, and Morton's neuroma have been reported. Similarly, clinical trial results of TRPV1 antagonists such as SB-705498 and AMG 517 have also been published recently. Overall, some molecules (e.g., capsaicin) demonstrated potential analgesia in certain conditions (postsurgical pain, postherpetic neuralgia, pain in diabetic neuropathy, osteoarthritis, bunionectomy, and Morton's neuroma), whereas others fell out of the clinic due to on-target liabilities or failed to demonstrate efficacy. This review summarizes recent advances and setbacks of TRPV1 agonists and antagonists in the clinic and predicts future directions.

Drugs used to treat Parkinson's disease, present status and future directions.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, after Alzheimer's disease. In PD, motor symptoms result from the degeneration and loss of pigmented dopaminergic neurons of the substantia nigra pars compacta of the basal ganglia. Other neuronal fields and neurotransmitter systems are also involved, including non-adrenergic, serotonergic and cholinergic neurons. Since the early 1960s the treatment of PD has been based on the pharmacologic replacement of dopamine accomplished with the precursor of dopamine, 3, 4-dihydroxy-L-phenylalanine (L-dopa). The addition of carbidopa, an inhibitor of the decarboxylase represented a tremendous improvement in therapy and is still a mainstay of the treatment of PD. Dopamine agonists may also be used, as well as inhibitors of monoamine oxidase-B or catechol-O-methyltransferase. Other medications include anticholinergics and amantadine. These therapies are only symptomatic and none halt or lessen dopaminergic neuron degeneration and the progression of the disease. This has prompted the search for novel and alternative pharmacological targets and neuroprotective therapies. In this context, there are data to suggest a benefit from glial cell line-derived neurotrophic factor, neuroimmumophilin ligands, minocycline, Coenzyme Q10, creatine, reduced glutathione, adenosine A2A receptor antagonists as well as glutamate release inhibitors. Restorative techniques to compensate for cell loss include tissue transplantation and gene transfer therapy. Due to the paucity of data regarding non-pharmacological approaches such as diet therapy or antioxidant therapy, these await more studies. There are also few studies on medicinal plants. Other areas of increasing importance would thus include the investigation of active constituents of plants and phytomedicines with a view to the discovery of new compounds. Finally, stem cell therapy may offer the promise of restoring functionality.

Promising avenues of therapeutics for bipolar illness.

Basic scientific advances in understanding the neuropsychobiology of bipolar disorder have given us a multitude of opportunities to explore and exploit new avenues of therapeutics. Pharmacotherapeutic approaches include: neuropeptides (agonists such as thyrotropin-releasing hormone and antagonists such as corticotropin-releasing hormone), neurotrophic factors (especially brain-derived neurotrophic factor), and glutamatergic mechanisms (such as riluzole, ketamine, and antagonists of the NR-2B subunit of the glutamate receptor). Physiological interventions that would offer alternatives to electroconvulsive therapy include: repeated transcranial magnetic stimulation, especially at more intense stimulation parameters; magnetic stimulation therapy (seizures induced more focally by magnetic rather than electrical stimulation with resulting reduced meaning loss); vagal nerve stimulation, and deep brain stimulation. However, these, as well as the panoply of existing treatments, require further intensive investigation to place each of them in the proper therapeutic sequence and combination for the individual patient, based on development of better clinical and biological predictors of response. Large clinical trial networks and development of systematic research in clinical practice settings, such as that featured by the National Cancer Institute for cancer chemotherapy, would greatly accelerate the progress in incorporating new, as well as existing, agents into the best treatment strategies. The bipolar disorders, which are increasingly recognized as complex, highly comorbid conditions with a high morbidity and mortality, of which the majority start in childhood and adolescence, are not likely to respond completely to any single new treatment agent, and new public health initiatives and research strategies are needed as much as any new single treatment advance.

Targets of cytoprotection in acute ischemic stroke: present and future.

Although the management of stroke has improved remarkably over the last decade due mainly to the advent of thrombolysis, most neuroprotective agents, although successful in animal studies, have failed in humans. Our increasing knowledge concerning the ischemic cascade is leading to a considerable development of pharmacological tools suggesting that each step of this cascade might be a target for cytoprotection. Glutamate has long been recognized to play key roles in the pathophysiology of ischemia. However, although some trials are still ongoing, the results from several completed trials with drugs interfering with the glutamatergic pathway have been disappointing. Regarding the inhibition of glutamate release as a possible target for cytoprotection, it might be afforded either by decreasing glutamate efflux or by increasing glutamate uptake. In this context, it has been shown that glutamate transport is the primary and only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels. This transport is executed by the five high-affinity, sodium-dependent plasma membrane glutamate transporters. Among them, the transporter EAAT2 is responsible for up to 90% of all glutamate transport. We will discuss the effect of different neuroprotective tools (membrane stabilizers or endogenous neuroprotection) affecting glutamate efflux and/or expression of EAAT2. We will also describe the finding of a novel polymorphism in the EAAT2 promoter region which could be responsible for differences in both gene function and regulation under pathological conditions such as cerebral ischemia, and which might well account for the failure of glutamate antagonists in the clinical practice. These results may possess important therapeutic implications in the management of patients at risk of ischemic events, since it has been demonstrated that those patients with progressing stroke have higher plasma concentrations of glutamate which remain elevated up to 24 h when compared to the levels in patients without neurological deterioration.