Commentary: Aripiprazole: The Second Wave of the Second-generation Antipsychotics.

Three cases are presented describing unique clinical responses to aripiprazole in comparison with other second-generation antipsychotics taken by each patient. One case involved an adverse reaction of problem gambling behavior, the second an enhanced antipsychotic response in delusional disorder, and the third a reversal of weight gain that occurred while the patient continued taking olanzapine. Aripiprazole was the first of a subgroup of atypical antipsychotics that are mixed agonists and antagonists of dopamine, likely contributing to unusual responses in some patients.

The 200-year journey of Parkinson disease: Reflecting on the past and looking towards the future.

It took almost 100 years before a meaningful advance occurred in any basic science understanding of Parkinson disease (PD) following James Parkinson's description in 1817. The Lewy body was described in 1912, and the substantia nigra was found to be depigmented with neuronal loss and gliosis in 1919. The link between dopamine and PD began in 1957, 140 years after Parkinson's Essay. Arvid Carlsson and Oleh Hornykiewicz were the major pioneers. The revolutionary therapeutic breakthrough was the introduction of high dosage levodopa therapy by George Cotzias in 1967. Following 40 years of the dopa/dopamine era, we have entered the era of alpha-synuclein, the protein present in Lewy bodies. Heiko Braak found that alpha-synuclein accumulates initially in the olfactory system and lower brainstem and then travels in an anatomic pattern to involve other regions of the brain and thereby cause progressive symptoms. Alpha-synuclein was somehow converted to a rogue protein. Where this originates and how it is propagated are under intense investigation. At the same time that the alpha-synuclein era was developing, clinical advances took place by recognizing PD as hosting a wide variety of nonmotor features with eventual cognitive impairment in many. Therapeutics has also evolved. Although the most effective therapy for the motor features remains levodopa, surgical approaches and drugs for nonmotor problems continue to expand our ability to treat people with PD. We can expect therapeutic advances in neuroprotection as the basic science discoveries uncovered in the alpha-synuclein era are translated into effective treatments.

Milestones in Parkinson's disease therapeutics.

In the mid-1980s, the treatment of Parkinson's disease was quite exclusively centered on dopatherapy and was focusing on dopamine systems and motor symptoms. A few dopamine agonists and a monoamine oxidase B inhibitor (selegiline) were used as adjuncts in advanced Parkinson's disease. In the early 2010s, levodopa remains the gold standard. New insights into the organization of the basal ganglia paved the way for deep brain stimulation, especially of the subthalamic nucleus, providing spectacular improvement of drug-refractory levodopa-induced motor complications. Novel dopamine agonists (pramipexole, ropinirole, rotigotine), catecholmethyltransferase inhibitors (entacapone), and monoamine oxidase B inhibitors (rasagiline) have also been developed to provide more continuous oral delivery of dopaminergic stimulation in order to improve motor outcomes. Using dopamine agonists early, before levodopa, proved to delay the onset of dyskinesia, although this is achieved at the price of potentially disabling daytime somnolence or impulse control disorders. The demonstration of an antidyskinetic effect of the glutamate antagonist amantadine opened the door for novel nondopaminergic approaches of Parkinson's disease therapy. More recently, nonmotor symptoms (depression, dementia, and psychosis) have been the focus of the first randomized controlled trials in this field. Despite therapeutic advances, Parkinson's disease continues to be a relentlessly progressive disorder leading to severe disability. Neuroprotective interventions able to modify the progression of Parkinson's disease have stood out as a failed therapeutic goal over the last 2 decades, despite potentially encouraging results with compounds like rasagiline. Newer molecular targets, new animal models, novel clinical trial designs, and biomarkers to assess disease modification have created hope for future therapeutic interventions.

[Madopar: more than 20 years]. / Más de 20 años de Madopar.

OBJECTIVE: To review the main landmarks which led to the introduction of levadopa in the the treatment of Parkinson's disease and the impact of levadopatherapy. DEVELOPMENT: The introduction of levadopa was based on the results of basic scientific investigations in neurochemistry and neuropharmacology. In 1959 the possibility of dopamine being a neurotransmissor, and the role it plays in motor control, had been discovered. In 1960, Hornykiewiez and Ehringer published a paper on the existence of a marked deficit of dopamine in the caudate nucleus and putamen of patients with Parkinson's disease. Almost simultaneously, Birkmayer and Barbeau treated their patients with levadopa for the first time. However, levadopa was not introduced into clinical practice until 1967 and 1969 when Cotzias published papers establishing the principles of levadopatherapy as we now know it. Introduction of levadopa produced a markedly beneficial effect on the course and mortality of Parkinson's disease. However, it was soon seen that progression of the disease was not halted and that undesirable side effects appeared in patients on long-term treatment. This has led to the development of strategies to prolong the beneficial effects of levadopa and minimize its side effects. CONCLUSION: More than 25 years after the introduction of levadopatherapy, it is still the mainstay of the treatment of Parkinson's disease, in combination with other medical and surgical treatment. Definitive treatment, however, will have to wait until the cause of this illness is fully understood.