mdl-100907 and Hyperprolactinemia

The overall outcome in schizophrenia is generally poor, despite the undisputed efficacy of antipsychotics in treating the acute symptoms of psychosis. There remains a subset of patients who are refractory to treatment. Also, for most patients treatment is not effective against the full spectrum of symptoms including negative and cognitive symptoms, and severe functional deficits persist. Further, while the newer drugs produce fewer motor side effects, other safety and tolerability concerns have emerged. Since the advent of antipsychotic therapy in the early 1950s, subsequent advances have been modest. While the mechanism of action of the first-generation antipsychotics appears closely linked to D2 antagonism, the second-generation antipsychotics have broader receptor-binding profiles, particularly 5-HT receptor antagonism. Attempts are now being made to develop antipsychotics with a wider spectrum of efficacy and a more favourable safety and tolerability profile by further exploring the therapeutic potential of D2 and 5-HT2 receptors, as well as investigating other putative mechanisms of action. This article adds to the current literature by providing an up-to-date review of antipsychotic drugs currently in development, focusing on the findings to date for compounds that are presently in Phase III clinical trials. While no exciting breakthroughs appear imminent, several drugs in early development have great potential.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Cognition; Dopamine D2 Receptor Antagonists; Drug Discovery; Drugs, Investigational; Humans; Hyperprolactinemia; Motor Activity; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists

Many dopamine antagonists are proven acute migraine treatments. Genetic studies also imply that polymorphisms in dopamine genes (DRD2 receptors) in persons with migraine may create dopamine hypersensitivity. However, treatment is limited by the adverse event profiles of conventional neuroleptics including extrapyramidal symptoms, anticholinergic and antihistaminergic effects, hyperprolactinemia, and prolonged cardiac QT interval. Atypical neuroleptics cause less extrapyramial symptoms and some atypical neuroleptics, including olanzapine and quetiapine, may be beneficial as both acute and preventive migraine treatment. The combination of prochlorperazine, indomethacin, and caffeine is effective in the treatment of the acute migraine attack. The mechanism of action by which neuroleptics relieve headache is probably related to dopamine D2 receptor antagonist. Other actions via serotonin (5HT) receptor antagonists may also be important, particularly for migraine prevention. Additional studies to clarify the mechanism of action of neuroleptics in migraine could lead to new drugs and better management of migraine.

Topics: Antipsychotic Agents; Benzodiazepines; Brain; Caffeine; Dibenzothiazepines; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Interactions; Female; Humans; Hyperprolactinemia; Indomethacin; Male; Migraine Disorders; Neural Pathways; Olanzapine; Prochlorperazine; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists; Treatment Outcome

Topics: Antipsychotic Agents; Aripiprazole; Drug Therapy, Combination; Haloperidol; Humans; Hyperprolactinemia; Piperazines; Quinolones; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Synaptic Transmission