The New England Journal of Medicine features a review of dystonia, a movement disorder that causes sustained muscle contractions, repetitive twisting movements, and abnormal postures of the trunk, neck, face, or arms and legs. It is a condition that may often be confused with spasticity or rigidity, and sometimes, may even be mistakenly attributed to psychogenic causes. This article discusses the following:

• Clinical Features
• Classification (Primary dystonia, primary generalised torsion dystonia, primary focal dystonia, secondary dystonia,
  heredodegenerative disorders, drug-induced dystonia, acquired structural lesions, dystonia-plus syndromes, paroxysmal dystonia).
• Pathophysiology
• Evaluation
• Treatment (pharmacotherapy, botulinum toxin, surgery, physical therapies)

The article notes that acute drug-induced dystonia can be caused by levodopa, dopamine agonists, antipsychotic drugs, anticonvulsant agents, SSRIs, and rarely by other miscellaneous drugs. In addition, persistent tardive dystonia may occur after prolonged use of dopamine-receptor–blocking antipsychotic drugs and metoclopramide. It may also occur as a result of the toxic effects of manganese, carbon monoxide, carbon disulfide, and other chemicals.

In terms of drug treatment, it is recognised that except for dopa-responsive dystonia and Wilson's disease, there is no specific pharmacological treatment for dystonia. For patients with generalised or focal dystonia of unknown cause, a trial of carbidopa–levodopa (one 25/100mg TDS) is recommended to establish or rule out dopa-responsive dystonia. Treatments that have been tried include:

• High-dose anticholinergic treatment with trihexyphenidyl (6 to 80 mg/d) or benztropine (4 to 8 mg/d) - partially effective in up to 40-50% of patients with primary or secondary dystonia; children can tolerate higher doses than adults, with greater benefit and fewer side effects.

• Benzodiazepines, baclofen, diphenhydramine, carbamazepine, mexiletine, gabapentin, dopamine agonists, and dopamine antagonists have been used in open-label trials without consistent benefit.

• Tetrabenazine produced marked improvement in two thirds of patients with focal and generalised dystonia in a large, uncontrolled retrospective study, but it was associated with frequent side effects.

• Intrathecal baclofen has been used with mixed success in children and adults whose dystonia is combined with spasticity.

• Botulinum toxin serotypes A and B when injected into dystonic muscles, reduce muscle spasm without systemic side effects. The authors consider this the treatment of choice for cervical dystonia, blepharospasm, spasmodic dysphonia, oromandibular dystonia, and limb dystonia, because it provides long-term benefit in 70 to 90% of patients. They add that similar benefit has been seen with either serotype A or B in patients with cervical dystonia; it may also be used in patients with generalised or multifocal dystonia to treat selected muscles.
Link: http://content.nejm.org/cgi/content/full/355/8/818

Ever-happy mice may hold key to new treatment of depression

Source: McGill University Health Centre

A new breed of permanently 'cheerful' mouse is providing hope of a new treatment for clinical depression. TREK-1 is a gene that can affect transmission of serotonin in the brain. Serotonin is known to play an important role in mood, sleep and sexuality. By breeding mice with an absence of TREK-1, researchers were able create a depression-resistant strain. The details of this research, which involved an international collaboration with scientists from the University of Nice, France, are published in Nature Neuroscience this week.

"Depression is a devastating illness, which affects around 10% of people at some point in their life," says Dr. Guy Debonnel an MUHC psychiatrist, professor in the Department of Psychiatry at McGill University, and principal author of the new research. "Current medications for clinical depression are ineffective for a third of patients, which is why the development of alternate treatments is so important."

Mice without the TREK-1 gene ('knock-out' mice) were created and bred in collaboration with Dr. Michel Lazdunski, co-author of the research, in his laboratory at the University of Nice, France. "These 'knock-out' mice were then tested using separate behavioral, electrophysiological and biochemical measures known to gauge 'depression' in animals," says Dr. Debonnel. "The results really surprised us; our 'knock-out' mice acted as if they had been treated with antidepressants for at least three weeks."

This research represents the first time depression has been eliminated through genetic alteration of an organism. "The discovery of a link between TREK-1 and depression could ultimately lead to the development of a new generation of antidepressant drugs," noted Dr. Debonnel.