Antipsychotic drugs development

Shen, W.W. (1999a) A history of antipsychotic drug development. Compr Psychiatry 40 407-414. 

Serotonin and Dopamine Interactions in Rodents and Primates Implications for Psychosis and Antipsychotic Drug Development... 

Hartman DS, Civelli O. 1996. Molecular attributes of dopamine receptors New potential for antipsychotic drug development. Ann Med 28 211-219. 

From American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004 27 596-601, with permission. 

Divalproex sodium is comprised of sodium valproate and valproic acid. The delayed-release and extended-release formulations are converted in the small intestine into valproic add, which is the systemically absorbed form. It was developed as an antiepileptic drug, but also has efficacy for mood stabilization and migraine headaches. It is FDA-approved for the treatment of the manic phase of bipolar disorder. It is generally equal in efficacy to lithium and some other drugs for bipolar mania. It has particular utility in bipolar disorder patients with rapid cycling, mixed mood features, and substance abuse comorbidity. Although not FDA-approved for relapse prevention, studies support this use, and it is widely prescribed for maintenance therapy. Divalproex can be used as monotherapy or in combination with lithium or an antipsychotic drug.31... 

Tardive dyskinesia A chronic disorder of the nervous system characterized by involuntary jerky or writhing movements of the face, tongue, jaws, trunk, and limbs, usually developing as a late side effect of prolonged treatment with antipsychotic drugs. 

Udomratn, P., Vasiknanonte, S., Lambert, T., Ng, C. 8cFreeman, N. (2004). Pattern ofprescribing antipsychotic drugs in a developing country a report from Thailand. European Psychiatry, 19(suppl 1), 194S. 

Green, M. F. Braff, D. L. (2001). Translating the basic and clinical cognitive neuroscience of schizophrenia to drug development and clinical trials of antipsychotic medications. Biol. 

The 1950s represented a golden age for pharmacotherapy. The first antipsychotic drug, chlorpromazine, was developed in the first few years of that decade (Chapter 11), the... 

Another serious side effect of clozapine is a risk of seizures. This mainly occurs at higher doses of the drug, and having a seizure is not necessarily a sufficient reason to stop clozapine permanently. If the clozapine has been especially helpful, an anticonvulsant can be added to protect against further seizures. Valproate (Depakote) may be best in this regard because it not only provides protection from seizures but also may help to relieve some of the symptoms of schizophrenia. Recently, it has become clear that two atypical antipsychotic drugs, clozapine and olanzapine, are associated with an increased risk for the development of type II diabetes. 

However, experimental studies of the 5-HT3 antagonists on dopamine autoreceptors may eventually offer new leads to the development of novel antipsychotic drugs. 

Tardive dyskinesia (TD) TD, a syndrome consisting of potentially irreversible, involuntary dyskinetic movements, may develop in patients treated with antipsychotic drugs. Both the risk of developing TD and the likelihood that it will become irreversible are increased as duration of treatment and total cumulative dose administered increase. 

Extrapyramidal symptoms (EPS) Dystonic reactions develop primarily with the use of traditional antipsychotics. EPS has occurred during the administration of haloperidol and pimozide frequently, often during the first few days of treatment. Neuroleptic malignant syndrome (NMS) A potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, rhabdomyolysis, and acute renal failure. 

Altered startle reactivity and attenuation of the inhibition of the startle reflex by an acoustic prepulse has been observed in psychiatric patients, e.g. in schizophrenia (Braff et al. 1978). Disrupted prepulse inhibition in rats can be normalized by antipsychotics and this paradigm is being used as an animal model for drug development. Interestingly, a2c-KO mice had enhanced startle responses, diminished prepulse inhibition, and shortened attack... 

Levodopa is widely used for treatment of all types of parkinsonism except those associated with antipsychotic drug therapy. However, as parkinsonism progresses, the duration of benefit from each dose of levodopa may shorten (wearing-off effect). Patients can also develop sudden, unpredictable fluctuations between mobility and immobility (on-off effect). In a matter of minutes, a patient enjoying normal or nearly normal mobility may suddenly develop a severe degree of parkinsonism. These symptoms are likely due to the... 

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